Opioid agonists and uses thereof

ABSTRACT

Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.

This application is a divisional of U.S. patent application Ser. No.15/603,942, filed May 24, 2017, now allowed, which is a continuation ofU.S. patent application Ser. No. 15/039,686, filed May 26, 2016, nowU.S. Pat. No. 9,688,638, which is a 35 U.S.C. § 371 application ofInternational Application No. PCT/IN2014/000739, filed Nov. 27, 2014,designating the United States, which claims the benefit of priority toIndian Patent Application No. 401/DEL/2014, filed Feb. 13, 2014, and toIndian Patent Application No. 3456/DEL/2013, filed Nov. 27, 2013, thedisclosures of which are all incorporated herein by reference in theirentireties.

The present disclosure relates to novel compounds and to their use asagonists of the kappa opioid receptor, the mu opioid receptor, or mixedagonists of both receptors. The disclosure also relates to methods forpreparation of the compounds and to pharmaceutical compositionscontaining such compounds. The compounds described herein relate toand/or have application(s) in (among others) the fields of drugdiscovery, pharmacotherapy, physiology, organic chemistry and polymerchemistry.

Opioid agonists, such as morphine, have long been used to treat patientssuffering from pain. Opioid agonists exert their analgesic and otherpharmacological effects through interactions with opioid receptors, ofwhich there are three main classes: mu (μ) receptors, kappa (κ)receptors, and delta (δ) receptors. Many of the clinically used opioidagonists are relatively selective for mu receptors, although opioidagonists typically have agonist activity at other opioid receptors(particularly at increased concentrations).

Pharmacologically, opioid agonists represent an important class ofagents employed in the management of pain. Opioid agonists currentlyused in analgesia, however, contain considerable addictive propertiesthat complicate and limit their use in therapeutic practice. Themedical, social and financial complications arising from opioid abuseimpose severe constraints on the ability of physicians to prescribeopioids for use in chronic pain.

Kappa opioid agonists that exhibit full agonist properties at the kappaopioid receptor have been widely shown to be efficacious in preclinicalmodels of pain, particularly visceral pain. Kappa opioid agonists areunderstood to lack several of the side effects of mu opioid agonists,including abuse liability, gastrointestinal transit inhibition andrespiratory depression. Kappa opioid agonists, however, are understoodto produce complicating CNS mediated side effects, such as dysphoria andsedation at analgesic doses. As a result, the presence of these sideeffects has hindered the development of selective kappa opioid agonistsas clinically useful analgesics.

Mixed mu and kappa opioid agonist that exhibit full agonist propertiesat the respective opioid receptors have also been shown to beefficacious in preclinical models of pain, including visceral pain.However, despite the combined analgesic properties a mixed mu and kappaopioid agonists may demonstrate, they are understood to produce severalside effects related to both mu and kappa opioid receptor mechanisms,including abuse liability, respiratory depression, gastrointestinaltransit inhibition, sedation and dysphoria.

Beyond analgesia, kappa agonists have shown anti-inflammatory effects invivo. Additionally, asimadoline, a kappa opioid agonist that ismoderately restricted to the periphery, is currently undergoing studiesfor the treatment of irritable bowel syndrome. Due to its limited CNSentry, asimadoline may reduce the extent of side effects associated withless restricted kappa agonists, though studies are still ongoing.Additional known kappa opioid agonists, such as enadoline andspiradoline, enter the CNS (Central Nervous System) causing dysphoria,and may have contributed to not being developed clinically. Further,while mixed agonists (acting on kappa and mu receptors) have beenmarketed, including pentazocine, to date, no full kappa agonist has beenapproved for use in humans for the treatment of pain.

The incorporation of a poly(ethylene glycol) moiety into a smallmolecule scaffold has been utilized to modify the rate of CNS entry ofseveral classes of molecules. See U.S. Patent Application PublicationNo. 2005/0136031 and U.S. Patent Application Publication No.2010/0048602. The sites of incorporation and further modifications tothe molecules, however, have differing effects on the overall activityand pharmacological properties of the resulting molecule.

In view of the above, there remains a need for peripherally actingopioid agonists that retain sufficient efficacy to treat visceral painand other symptoms or disease states associated with the opioidreceptor, while reducing the CNS side effects. The present inventionseeks to address these and other needs.

In one or more embodiments, a compound selected from the formula:

wherein:

R¹ is selected from hydrogen, optionally substituted alkyl, optionallysubstituted aryl, and X-POLY;

R³ is selected from hydroxyl, optionally substituted alkyl, optionallysubstituted amino, optionally substituted heterocyclyl, and —X-POLY;

R⁵ is selected from hydrogen and —X-POLY;

or R¹ and R³ are taken together with their intervening atoms to form afused, optionally substituted heteroaryl or optionally substitutedheterocyclyl; or R³ and R⁵ are taken together with their interveningatoms to form a fused, optionally substituted heteroaryl;

R² is selected from optionally substituted alkyl and —X-POLY;

is optionally a single bond or a double bond;

G is —O—R⁴ or —NH—R⁴ when

represents a single bond, or G is ═O or ═N—R⁴ when

represents a double bond;

X is a spacer moiety and is preferably selected from a covalent bond,—NHC(O)—, —NH—, and —O—;

POLY is a water soluble, non-peptidic oligomer; and

R⁴ is -L-POLY or —X-POLY, wherein L is an optional amino acid residue,

provided that one of R¹, R², R³, R⁴, and R⁵ comprises a POLY group; andpharmaceutically acceptable salts and solvates thereof.

In certain embodiments of Formula I, R¹ is selected from hydrogen,optionally substituted alkyl, optionally substituted aryl, and —X-POLY;R² is selected from optionally substituted alkyl and —X-POLY; R³ isselected from hydroxyl, optionally substituted alkyl, optionallysubstituted amino, optionally substituted heterocyclyl, and —X-POLY; orR¹ and R³ are taken together with their intervening atoms to form afused, optionally substituted heteroaryl or optionally substitutedheterocyclyl; or R³ and R⁵ are taken together with their interveningatoms to form a fused, optionally substituted heteroaryl;

is optionally a single bond or a double bond; G is —O—R⁴ or NH—R⁴ when

represents a single bond or G is ═O or ═N—R⁴ when

represents a double bond; X is selected from a covalent bond, —NHC(O)—,—NH—, and —O—; POLY is a water soluble, non-peptidic oligomer; R⁴ is-L-POLY or —X-POLY, wherein L is an optional amino acid residue; R⁵ isselected from hydrogen and —X-POLY; provided one of R¹, R², R³, R⁴, andR⁵ comprises a POLY group; and pharmaceutically acceptable salts andsolvates thereof.

In one or more embodiments of the invention, a composition is provided,the composition comprising (i) a compound as described herein, and,optionally, (ii) a pharmaceutically acceptable excipient.

In one or more embodiments of the invention, a composition of matter isprovided, the composition of matter comprising a compound as describedherein, wherein the compound is present in a dosage form.

In one or more embodiments of the invention, a method is provided, themethod comprising administering a compound as described herein to apatient in need thereof.

Additional embodiments of the present compounds, compositions, methods,and the like will be apparent from the following description, examples,and claims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims.

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like. As used herein, “lower alkyl” refers to an alkyl grouphaving from 1 to 6 carbon atoms. Specific examples of lower alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted alkyl” refers to an alkyl group having 1 to 5substituents (in certain embodiments 1, 2, or 3) selected from alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy,acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, keto,thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —X-POLY, —S(O)-alkyl,—S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl, —S(O)-heteroaryl,—S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl, —S(O)₂-aryl and—S(O)₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R is alkyl, aryl or heteroaryl and n is 0, 1, or 2.“Substituted lower alkyl” refers to a lower alkyl group defined above,substituted as defined for alkyl.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in certain embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like. The term “lower alkylene” refers to adiradical of a branched or unbranched saturated hydrocarbon chain, incertain embodiments, having 1, 2, 3, 4, 5 or 6 carbon atoms.

The terms “substituted alkylene” and “substituted lower alkylene” referto an alkylene group or lower alkylene group as defined above having 1to 5 substituents (in certain embodiments, 1, 2 or 3 substituents) asdefined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (incertain embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbonatoms) and having from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In certain embodiments, alkenyl groupsinclude ethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like. The term “loweralkenyl” refers to alkenyl as defined above having from 2 to 6 carbonatoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in certain embodiments, 1, 2, or 3substituents) as defined for substituted alkyl.

The term “substituted lower alkenyl” refers to a lower alkenyl group asdefined above having 1 to 5 substituents (in certain embodiments, 1, 2,or 3 substituents) as defined for substituted alkyl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (incertain embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbonatoms) and having from 1 to 6 carbon-carbon double bonds, e.g. 1, 2, or3 carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in certain embodiments, having from 2 to 20 carbon atoms(in certain embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbonatoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2, or 3carbon-carbon triple bonds. In certain embodiments, alkynyl groupsinclude ethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and thelike.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in certain embodiments, 1, 2, or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in certain embodiments, having from 2 to 20 carbon atoms(in certain embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbonatoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2, or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In certain embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like. The term “lower alkoxy”refers to the group R—O— in which R is optionally substituted loweralkyl. This term is exemplified by groups such as methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, andthe like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is optionally substituted alkyleneand Z is substituted alkenyl or substituted alkynyl, where substitutedalkyl, substituted alkenyl and substituted alkynyl are as definedherein.

The term “C₁₋₃ haloalkyl” refers to an alkyl group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In certainembodiments, C₁₋₃ haloalkyl includes, by way of example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, 3,3,3-trifluoropropyl,3,3-difluoropropyl, and 3-fluoropropyl.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in certain embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in certain embodiments, 1, 2 or 3 substituents), selected from alkyl,alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy,cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino,amino carbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —X-POLY, —S(O)-alkyl,—S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl, —S(O)-heteroaryl,—S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl, —S(O)₂-aryl and—S(O)₂-heteroaryl.

The term “substituted cycloalkyl” also includes cycloalkyl groupswherein one or more of the annular carbon atoms of the cycloalkyl grouphas an oxo group bonded thereto. In addition, a substituent on thecycloalkyl or cycloalkenyl may be attached to the same carbon atom as,or is geminal to, the attachment of the substituted cycloalkyl orcycloalkenyl to the 6,7-ring system. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1, or 2.

As used herein, “—X-POLY” refers to a water-soluble, nonpeptidicoligomer POLY attached through a linker “X”.

“Water soluble oligomer” indicates a non-peptidic oligomer that is atleast 35% (by weight) soluble, preferably greater than 70% (by weight),and more preferably greater than 95% (by weight) soluble, in water atroom temperature. It is most preferred, however, that the water-solubleoligomer is at least 95% (by weight) soluble in water or completelysoluble in water. With respect to being “non-peptidic,” an oligomer isnon-peptidic when it has less than 35% (by weight) of amino acidresidues.

The terms “monomer,” “monomeric subunit” and “monomeric unit” are usedinterchangeably herein and refer to one of the basic structural units ofa polymer or oligomer. In the case of a homo-oligomer, a singlerepeating structural unit forms the oligomer. In the case of aco-oligomer, two or more structural units are repeated—either in apattern or randomly—to form the oligomer. In certain embodiments, theoligomers used in connection with present the invention arehomo-oligomers. The water-soluble oligomer typically comprises one ormore monomers serially attached to form a chain of monomers. Theoligomer can be formed from a single monomer type (i.e., ishomo-oligomeric) or two or three monomer types (i.e., is co-oligomeric).

An “oligomer” is a molecule possessing from about 1 to about 50monomers, preferably from about 1 to about 30 monomers. In certainembodiments, an “oligomer” is a molecule possessing from about 2 toabout 50 monomers, preferably from about 2 to about 30 monomers. Thearchitecture of an oligomer can vary. Specific oligomers for use in theinvention include those having a variety of geometries such as linear,branched, or forked, to be described in greater detail below.

“PEG” or “polyethylene glycol,” as used herein, is meant to encompassany water-soluble poly(ethylene oxide). Unless otherwise indicated, a“PEG oligomer” or any polyethylene glycol is one in which substantiallyall (preferably all) monomeric subunits are ethylene oxide subunits,though, the oligomer may contain distinct end capping moieties orfunctional groups, e.g., for providing a site of covalent modificationor reaction with another compound. PEG oligomers for use in the presentinvention will comprise one of the two following structures:“—(CH₂CH₂O)_(n)—” or “—(CH₂CH₂O)_(n-1)CH₂CH₂—,” depending upon whetheror not the terminal oxygen(s) has been displaced, e.g., during asynthetic transformation. For the PEG oligomers, the variable (n) rangesfrom about 1 to 50, and the terminal groups and architecture of theoverall PEG can vary. When PEG further comprises a functional group, A,for linking to, e.g., a small molecule, the functional group whencovalently attached to a PEG oligomer does not result in formation of anoxygen-oxygen bond (—O—O—, a peroxide linkage).

The terms “end-capped” or “terminally capped” are interchangeably usedherein to refer to a terminal or endpoint of an oligomer having anend-capping moiety. Typically, although not necessarily, the end-cappingmoiety comprises a hydroxy or C₁₋₂₀ alkoxy group. Thus, examples ofend-capping moieties include alkoxy (e.g., methoxy, ethoxy andbenzyloxy), as well as aryl, alkyl, heteroaryl, cyclo, heterocyclo, andthe like. Further examples include C₁₋₃ haloalkyl and carboxy. Inaddition, saturated, unsaturated, substituted and unsubstituted forms ofeach of the foregoing are envisioned. Moreover, the end-capping groupcan also be a silane. The end-capping group can also comprise adetectable label. Such labels include, without limitation, fluorescers,chemiluminescers, moieties used in enzyme labeling, colorimetricmoieties (e.g., dyes), metal ions, radioactive moieties, and the like.Suitable detectors include photometers, films, spectrometers, and thelike. In addition, the end-capping group may contain a targeting moiety.

In the context of describing the consistency of oligomers in a givencomposition, “substantially” or “essentially” means nearly totally orcompletely, for instance, 95% or greater, in certain embodiments 97% orgreater, in certain embodiments 98% or greater, in certain embodiments99% or greater, and in certain embodiments 99.9% or greater.

“Monodisperse” refers to an oligomer composition wherein substantiallyall of the oligomers in the composition have a well-defined, singlemolecular weight and defined number of monomers, as determined bychromatography or mass spectrometry. Monodisperse oligomer compositionsare in one sense pure, that is, substantially comprising moleculeshaving a single and definable number of monomers rather than severaldifferent numbers of monomers (i.e., an oligomer composition havingthree or more different oligomer sizes). In certain embodiments, amonodisperse oligomer composition possesses a MW/Mn value of 1.0005 orless, and in certain embodiments, a MW/Mn value of 1.0000. By extension,a composition comprised of monodisperse compounds means thatsubstantially all oligomers of all compounds in the composition have asingle and definable number (as a whole number) of monomers rather thana distribution and would possess a MW/Mn value of 1.0005, and in certainembodiments, a MW/Mn value of 1.0000 if the oligomer were not attachedto a compound of the present invention. A composition comprised ofmonodisperse compounds can include, however, one or more substances suchas solvents, reagents, excipients, and so forth.

“Bimodal,” in reference to an oligomer composition, refers to anoligomer composition wherein substantially all oligomers in thecomposition have one of two definable and different numbers (as wholenumbers) of monomers rather than a distribution, and whose distributionof molecular weights, when plotted as a number fraction versus molecularweight, appears as two separate identifiable peaks. In certainembodiments, for a bimodal oligomer composition as described herein,each peak is generally symmetric about its mean, although the size ofthe two peaks may differ. Ideally, the polydispersity index of each peakin the bimodal distribution, Mw/Mn, is 1.01 or less, in certainembodiments 1.001 or less, in certain embodiments 1.0005 or less, and incertain embodiments a MW/Mn value of 1.0000. By extension, a compositioncomprised of bimodal compounds means that substantially all oligomers ofall compounds in the composition have one of two definable and differentnumbers (as whole numbers) of monomers rather than a large distributionand would possess a MW/Mn value of 1.01 or less, in certain embodiments1.001 or less, in certain embodiments 1.0005 or less, and in certainembodiments a MW/Mn value of 1.0000 if the oligomer were not attached toa compound of the present invention. A composition comprised of bimodalcompounds can include, however, one or more substances such as solvents,reagents, excipients, and so forth.

“Branched”, in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more oligomersrepresenting distinct “arms” that extend from a branch point.

“Forked” in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more functional groups(typically through one or more atoms) extending from a branch point.

A “branch point” refers to a bifurcation point comprising one or moreatoms at which an oligomer branches or forks from a linear structureinto one or more additional arms.

As used herein “X” is a spacer moiety including a covalent bond or agroup of 1-20 atoms. X may include, but is not limited to optionallysubstituted alkylene, optionally substituted alkenylene, optionallysubstituted alkynylene, optionally substituted alkoxy, hydroxyl,optionally substituted amino, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted ester, alkyl amine, dialkyl amine, keto, optionallysubstituted acyl, aminocarbonyl, carboxyalkyl, acyloxy, acylamino,alkoxycarbonylamino, aminocarbonylamino, and the like. It is understoodthat the spacer X will comprise diradicals of the respective groups.Exemplary spacer moieties include a covalent bond, —O—, —NH—, —S—,—C(O)—, —C(O)O—, —OC(O)—, —CH₂—C(O)O—, —CH₂—OC(O)—, —C(O)O—CH₂—,—OC(O)—CH₂—, —C(O)—NH—, —NH—C(O)—NH—, —O—C(O)—NH—, —C(S)—, —CH₂—,—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —O—CH₂—, —CH₂—O—,—O—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—,—CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,—CH₂—CH₂—CH₂—CH₂—O—, —C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—,—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—,—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—,—C(O)—NH—CH₂—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—CH₂—,—CH₂—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH₂—,—NH—C(O)—CH₂—O—, —CH₂—NH—C(O)—CH₂—, —CH₂—CH₂—NH—C(O)—CH₂—,—NH—C(O)—CH₂—CH₂—, —CH₂—NH—C(O)—CH₂—CH₂, —CH₂—CH₂—NH—C(O)—CH₂—CH₂—,—C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—, —O—C(O)—NH—, —O—C(O)—NH—CH₂—,—O—C(O)—NH—CH₂—CH₂—, —NH—CH₂—, —NH—CH₂—CH₂—, —CH₂—NH—CH₂—,—CH₂CHOHCH₂NH—, —CH₂—CH₂—NH—CH₂—, —C(O)—CH₂—, —C(O)—CH₂—CH₂—,—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—CH₂—,—CH₂—CH₂—C(O)—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—CH₂—, a bivalent cycloalkyl group,amino, substituted amino. Additional spacers include, acylamino, acyl,aryloxy, alkylene, amino, substituted amino, piperidino, andpyrrolidino. For purposes of the present invention, however, a group ofatoms is not considered a spacer when it is immediately adjacent to anoligomeric segment, and the group of atoms is the same as a monomer ofthe oligomer such that the group would represent a mere extension of theoligomer chain.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In certain embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4, or 5substituents (In certain embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, amino carbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —X-POLY, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,—S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In certain embodiments, the“heterocyclyl,” “heterocycle,” or “heterocyclic” group is linked to theremainder of the molecule through one of the heteroatoms within thering.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in certain embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, amino carbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —X-POLY, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,—S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2. Examples of heterocyclics includetetrahydrofuranyl, morpholino, piperidinyl, and the like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl.” The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine. The term “partiallysaturated heteroaryl” refers to a heteroaryl having a structureequivalent to an underlying aromatic heteroaryl which has had one ormore double bonds in an aromatic ring of the underlying aromaticheteroaryl saturated. Examples of partially saturated heteroarylsinclude dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in certain embodiments, 1, 2, or 3 substituents)selected from the group consisting alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, amino carbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —X-POLY, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,—S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl, benzothiazole or benzothienyl). Examples of nitrogenheterocyclyls and heteroaryls include, but are not limited to, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, phenanthroline, isothiazole, phenazine, isoxazole,phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like aswell as N-alkoxy-nitrogen containing heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂. The term “substituted amino”refers to the group —NRR where each R is independently selected from thegroup consisting of hydrogen, alkyl, —X-POLY, cycloalkyl, aryl,heteroaryl and heterocyclyl provided that both R groups are nothydrogen, or a group —Y—Z, in which Y is optionally substituted alkyleneand Z is alkenyl, cycloalkenyl or alkynyl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1, 2, or 3 substituents chosen from alkyl, alkenyl,alkynyl, —X-POLY, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “alkyl amine” refers to —NHR in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to —NRR in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group N═N═N.

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” or “carboxyl” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, —X-POLY, cyano or —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1, or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,—X-POLY, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and—S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0,1, or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or —C(O)O—cycloalkyl, where alkyl and cycloalkyl are as defined herein, and may beoptionally further substituted by alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, —X-POLY, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2, or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, —X-POLY, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1, or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,—X-POLY, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and—S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0,1, or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, —X-POLY, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2, or 3 substituents selected from alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, —X-POLY, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,—X-POLY, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and—S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0,1, or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents selected from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, —X-POLY, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1, or 2.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

The term “amino acid residue” refers to an amino acid that is altered bythe presence of one or more bonds that are not present in the parentamino acid. An example of a glycine residue is provided below:

Exemplary amino acid residues include residues of alanine, valine,leucine, isoleucine, glycine, threonine, serine, cysteine, methionine,tyrosine, phenylalanine, tryptophan, aspartic acid, glutamic acid,lysine, arginine, histidine, proline, and non-naturally occurring aminoacids. Included in this definition are both the representative L-aminoacids and D-amino acids.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

A “biological membrane” is any membrane, typically made from specializedcells or tissues, that serves as a barrier to at least some foreignentities or otherwise undesirable materials. As used herein a“biological membrane” includes those membranes that are associated withphysiological protective barriers including, for example: theblood-brain barrier (BBB); the blood-cerebrospinal fluid barrier; theblood-placental barrier; the blood-milk barrier; the blood-testesbarrier; and mucosal barriers including the vaginal mucosa, urethralmucosa, anal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa,and so forth. In certain contexts the term “biological membrane” doesnot include those membranes associated with the middle gastro-intestinaltract (e.g., stomach and small intestines) For example, in someinstances it may be desirable for a compound of the invention to have alimited ability to cross the blood-brain barrier, yet be desirable thatthe same compound cross the middle gastro-intestinal tract.

A “biological membrane crossing rate,” as used herein, provides ameasure of a compound's ability to cross a biological membrane (such asthe membrane associated with the blood-brain barrier). A variety ofmethods can be used to assess transport of a molecule across any givenbiological membrane. Methods to assess the biological membrane crossingrate associated with any given biological barrier (e.g., theblood-cerebrospinal fluid barrier, the blood-placental barrier, theblood-milk barrier, the intestinal barrier, and so forth), are known inthe art, described herein and/or in the relevant literature, and/or canbe determined by one of ordinary skill in the art.

“Pharmacologically effective amount,” “physiologically effectiveamount,” and “therapeutically effective amount” are used interchangeablyherein to mean the amount of a compound of the present invention aloneor present in a composition that is needed to provide a threshold levelof the compound in the bloodstream or in the target tissue. The preciseamount will depend upon numerous factors, e.g., the particular activeagent, the components and physical characteristics of the composition,intended patient population, patient considerations, and the like, andcan readily be determined by one skilled in the art, based upon theinformation provided herein and available in the relevant literature.

The term “patient,” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of acompound as described herein, and includes both humans and animals.

The compounds of the invention, if chiral, may be in a racemic mixture,or an optically active form, for example, a single optically activeenantiomer, or any combination or ratio of enantiomers (i.e., scalemicmixture). In addition, the compound may possess one or more geometricisomers. With respect to geometric isomers, a composition can comprise asingle geometric isomer or a mixture of two or more geometric isomers. Acompound for use in the present invention can be in its customary activeform, or may possess some degree of modification.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

The term “pharmaceutically acceptable salt” refers to non-toxic salts ofthe compounds of this invention. Pharmaceutically acceptable acidaddition salts may be prepared from inorganic and organic acids. Saltsderived from inorganic acids include hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like. Saltsderived from organic acids include acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluene-sulfonic acid, salicylic acid, and the like. Alsoincluded are salts with acidic amino acid such as aspartate andglutamate. Base addition salts include alkali metal salts such as sodiumsalt and potassium salt; alkaline earth metal salts such as magnesiumsalt and calcium salt; ammonium salt; organic basic salts such astrimethylamine salt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, and N,N′-dibenzylethylenediamine salt; and saltswith basic amino acid such as lysine salt and arginine salt. The saltsmay be in some cases hydrates or solvates.

The term “solvate” refers to a complex formed by the combining of acompound of the present invention and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound of the present invention and water.

Selected substituents comprising the compounds of Formula I may bepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Themultiple recitations may be direct or indirect through a sequence ofother substituents. Because of the recursive nature of suchsubstituents, theoretically, a large number of compounds may be presentin any given embodiment. One of ordinary skill in the art of medicinalchemistry understands that the total number of such substituents isreasonably limited by the desired properties of the compound intended.Such properties include, by way of example and not limitation, physicalproperties such as molecular weight, solubility or log P, applicationproperties such as activity against the intended target, and practicalproperties such as ease of synthesis. Recursive substituents may be anintended aspect of the invention. One of ordinary skill in the art ofmedicinal chemistry understands the versatility of such substituents. Tothe degree that recursive substituents are present in an embodiment ofthe invention, they may recite another instance of themselves, 0, 1, 2,3, or 4 times.

In some instances, names of compounds of the present disclosure areprovided using ACD/Name software for naming chemical compounds (AdvancedChemistry Development, Inc., Toronto, Canada). Other compounds orradicals may be named with common names or systematic or non-systematicnames. The naming and numbering of certain compounds of the disclosureis illustrated with a representative compound of the formula

which is named(6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one.

In some instances, names of compounds of the present disclosure areprovided using the chemical naming functionality of ChemBioDraw Ultra(Cambridgesoft, Waltham, Mass., Version 12.0) (e.g. Examples 1-28).Other compounds or radicals may be named with common names or systematicor non-systematic names. The naming and numbering of certain compoundsof the disclosure is illustrated with a representative compound of theformula

which is named:(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one.

In certain embodiments, a compound is selected from the formula:

wherein:

R¹ is selected from hydrogen, optionally substituted alkyl, optionallysubstituted aryl, and —X-POLY; R² is selected from optionallysubstituted alkyl and —X-POLY; R³ is selected from hydroxyl, optionallysubstituted alkyl, optionally substituted amino, optionally substitutedheterocyclyl, and —X-POLY; or R¹ and R³ are taken together with theirintervening atoms to form a fused, optionally substituted heteroaryl oroptionally substituted heterocyclyl; or R³ and R⁵ are taken togetherwith their intervening atoms to form a fused, optionally substitutedheteroaryl;

is optionally a single bond or a double bond; G is —O—R⁴ or —NH—R⁴ when

represents a single bond or G is ═O when

represents a double bond; X is selected from for example, a covalentbond, —C(O)—, —NHC(O)—, —NH—, —CH₂CHOHCH₂NH—, and —O—; POLY is a watersoluble, non-peptidic oligomer; R⁴ is -L-POLY or —X-POLY, wherein L isan optional amino acid residue; R⁵ is selected from hydrogen and—X-POLY; provided one of R¹, R², R³, R⁴, and R⁵ comprises a POLY group;and pharmaceutically acceptable salts and solvates thereof.

In certain embodiments of a compound of Formula I, R⁵ is hydrogen.

In certain embodiments of a compound of Formula I, R² is alkyl.

In certain embodiments of a compound of Formula I, R² iscyclopropylmethyl.

In certain embodiments of a compound of Formula I, G is —O— and

represents a double bond.

In certain embodiments of a compound of Formula I, R¹ is hydrogen.

In certain embodiments of a compound of Formula I, R³ is selected fromoptionally substituted alkyl, optionally substituted amino, and —X-POLY.

In certain embodiments of a compound of Formula I, R³ is optionallysubstituted amino.

In certain embodiments of a compound of Formula I, R³ is aminosubstituted with an optionally substituted aryl or optionallysubstituted alkyl.

In certain embodiments of a compound of Formula I, R³ is aminosubstituted with an optionally substituted phenyl.

In certain embodiments, the compound of Formula I is selected from acompound of the formula

wherein q is an integer from 1 to 3; each R^(a) is independentlyselected from optionally substituted amino, halo, optionally substitutedalkyl, and —X-POLY; X is selected from a covalent bond, —NH— or —O—;POLY is a water soluble, non-peptidic oligomer; and wherein only oneR^(a) is X-POLY.

In certain embodiments of the compound of Formula II, q is 1.

In certain embodiments of the compound of Formula II, X is —NH—. Incertain embodiments of the compound of Formula II, X is —O—.

In certain embodiments of the compound of Formula II, POLY is apoly(alkylene oxide) oligomer. In certain embodiments of the compound ofFormula II, POLY is a poly(ethylene oxide) oligomer. In certainembodiments of the compound of Formula II, POLY is capped with anoptionally substituted alkyl. In certain embodiments of the compound ofFormula II, POLY is capped with a methyl, trifluoromethyl, or methylsubstituted with a carboxy group.

In certain embodiments, the compound of Formula I or Formula II isselected from a compound of the formula

wherein R is selected from methyl, trifluoromethyl, and methylsubstituted with a carboxy group; n is an integer from 1 to 30; and X isselected from —O— or —NH—.

In certain embodiments of the compound of Formula III, X is —O—. Incertain embodiments of the compound of Formula III, X is —NH—.

In certain embodiments of the compound of Formula III, n is an integerfrom 1 to 10.

In certain embodiments, the compound of Formula I, II, or III isselected from a compound of the formula

wherein n is an integer from 1 to 30. In certain embodiments of thecompound of Formula IV, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R³ is an optionallysubstituted alkyl. In certain embodiments of a compound of Formula I, R³is an optionally substituted lower alkyl. In certain embodiments of acompound of Formula I, R³ is a lower alkyl group substituted with anoptionally substituted amino group or an optionally substitutedacylamino group.

In certain embodiments, the compound of Formula I is selected from acompound of the formula

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula V, n is an integer from 1 to 10.

In certain embodiments, the compound of Formula I is selected from acompound of the formula

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula VI, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R³ is —X-POLY. Incertain embodiments, the compound of Formula I is selected from acompound of the formula

wherein X is selected from —O—, —CH₂CHOHCH₂NH—, —NHC(O)—, and —NH—; andPOLY is a poly(alkylene oxide) oligomer. In certain embodiments of acompound of Formula VII, X is —O—. In certain embodiments of a compoundof Formula VII, X is —NH—. In certain embodiments of a compound ofFormula VII, X is —NHC(O)—. In certain embodiments of a compound ofFormula VII, X is —CH₂CHOHCH₂NH—. In certain embodiments the compound ofFormula VII is selected from a compound of the formula

wherein X is selected from —O—, —NHC(O)—, —CH₂CHOHCH₂NH—, and —NH—; andn is an integer from 1 to 30. In certain embodiments of a compound ofFormula VIII, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R¹ and R³ are takentogether with their intervening atoms to form a fused, optionallysubstituted heteroaryl or optionally substituted heterocyclyl. Incertain embodiments of a compound of Formula I, R¹ and R³ are takentogether with their intervening atoms to form a fused, optionallysubstituted heteroaryl. In certain embodiments of a compound of FormulaI, R¹ and R³ are taken together with their intervening atoms to form afused, optionally substituted heterocyclyl. In certain embodiments of acompound of Formula I, the heteroaryl or heterocyclyl is substitutedwith an optionally substituted amino group. In certain embodiments thecompound of Formula I is selected from a compound of the formula:

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula IX, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R³ is OH.

In certain embodiments of a compound of Formula I, R³ is OH and R¹ isselected optionally substituted alkyl, optionally substituted aryl, and—X-POLY. In certain embodiments of a compound of Formula I, R¹ isoptionally substituted lower alkyl. In certain embodiments of a compoundof Formula I, R¹ is optionally substituted methyl. In certainembodiments the compound of Formula I is selected from a compound of theformula

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula X, n is 1 to 10.

In certain embodiments of a compound of Formula I, R¹ is selected fromphenyl substituted with 1 to 3 substituents chosen from halo and—X-POLY. In certain embodiments of a compound of Formula I, R¹ isselected from phenyl substituted with 1 to 3 substituents chosen fromhalo and —X-POLY and R³ is hydroxyl. In certain embodiments of acompound of Formula I, R¹ is selected from phenyl substituted with 1 to3 substituents chosen from halo and —O—(CH₂CH₂O)_(n)CH₃, where n is aninteger from 1 to 30.

In certain embodiments the compound of Formula I is selected from acompound of the formula:

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula XI, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R³ is OH and R⁵ isX-POLY. In certain embodiments the compound of Formula I, is selectedfrom a compound of the formula:

wherein X is selected from —O— and —NH—, and n is an integer from 1 to30. In certain embodiments of a compound of Formula XII, n is an integerfrom 1 to 10. In certain embodiments X is —O—. In certain embodiments, Xis —NH—.

In certain embodiments of a compound of Formula I, R² is —X-POLY. Incertain embodiments of a compound of Formula I, G is —O— and

is a double bond. In certain embodiments of a compound of Formula I, R¹is hydrogen. In certain embodiments of a compound of Formula I, R⁵ ishydrogen. In certain embodiments of a compound of Formula I, R³ is —OH.

In certain embodiments the compound of Formula I, is selected from acompound of the formula:

wherein X is selected from a covalent bond and —C(O)—; and POLY is apoly(alkylene oxide) oligomer.

In certain embodiments of a compound of Formula I, the compound isselected from a compound of the formula:

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula XIV, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I,

is a single bond. In certain embodiments of a compound of Formula I, R¹is hydrogen. In certain embodiments of a compound of Formula I, R² iscyclopropylmethyl. In certain embodiments of a compound of Formula I, R³is —OH. In certain embodiments of a compound of Formula I, R⁵ ishydrogen. In certain embodiments the compound of Formula I is selectedfrom a compound of the formula:

wherein AA is an amino acid residue; and n is an integer from 1 to 30.In certain embodiments of a compound of Formula XV, AA is a glycineresidue. In certain embodiments of a compound of Formula XV, n is 1 to10.

In certain embodiments of a compound of Formula I, R³ is aminosubstituted with a substituted lower alkyl.

In certain embodiments, the compound of Formula I is selected from acompound of the formula

wherein q is an integer from 1 to 3; each R^(a) is independentlyselected from optionally substituted amino, halo, optionally substitutedalkyl, and —X—(CH₂CH₂O)_(n)CH₃; X is selected from a covalent bond, —NH—or —O—; and n is an integer from 1 to 30; wherein one R^(a) is—X—(CH₂CH₂O)_(n)CH₃. In certain embodiments of a compound of FormulaXVI, n is 1 to 10. In certain embodiments of a compound of Formula XVI,q is 1. In certain embodiments of a compound of Formula XV, X is —O—.

In certain embodiments, the compound of Formula XVI is selected from acompound of the formula

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula XVII, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, R³ is an optionallysubstituted heterocyclyl. In certain embodiments of a compound ofFormula I, R³ is a heterocyclyl substituted with —X-POLY. In certainembodiments of a compound of Formula I, R³ is a piperazinyl groupsubstituted with —X-POLY. In certain embodiments, the compound ofFormula I is selected from a compound of the formula

wherein n is 1 to 30. In certain embodiments of a compound of FormulaXVIII, n is 1 to 10.

In certain embodiments of a compound of Formula I, R³ and R⁵ are takentogether with their intervening atoms to form a fused, optionallysubstituted heteroaryl. In certain embodiments of a compound of FormulaI, the heteroaryl is substituted with an optionally substituted aminogroup. In certain embodiments the compound of Formula I is selected froma compound of the formula:

wherein n is an integer from 1 to 30. In certain embodiments of acompound of Formula XIX, n is an integer from 1 to 10.

In certain embodiments of a compound of Formula I, the compound isselected from a compound of the formula

wherein R⁶ is an optionally substituted alkyl or an optionallysubstituted heterocyclyl. In certain embodiments, R⁶ is an optionallysubstituted lower alkyl. In certain embodiments, R⁶ is a lower alkylsubstituted with 1 to 5 substituents selected from hydroxyl, loweralkoxy, halogen, and lower alkyl. In certain embodiments, R⁶ is anisopropyl or t-butyl group, substituted with 1 to 3 hydroxyl groups. Incertain embodiments of a compound of Formula XX, R⁶ is an optionallysubstituted heterocyclyl. In certain embodiments, R⁶ is a heterocyclylsubstituted with —X—(CH₂CH₂O)_(n)CH₃; wherein X is selected from acovalent bond, —NH— or —O—; and n is an integer from 1 to 30. In certainembodiments, R⁶ is a piperidinyl group substituted with—X—(CH₂CH₂O)_(n)CH₃; wherein X is selected from a covalent bond, —NH— or—O—; and n is an integer from 1 to 30. In certain embodiments, R⁶ is apiperidinyl group substituted with —X—(CH₂CH₂O)_(n)CH₃; wherein X is acovalent bond; and n is an integer from 1 to 10. In certain embodiments,the substituted heterocyclyl group is a substituted piperidin-4-yl.

In certain embodiments of a compound of Formula I,

is a single bond. In certain embodiments of a compound of Formula I, R¹is hydrogen. In certain embodiments of a compound of Formula I, R² iscyclopropylmethyl. In certain embodiments of a compound of Formula I, R³is —OH. In certain embodiments of a compound of Formula I, R⁵ ishydrogen. In certain embodiments the compound of Formula I is selectedfrom a compound of the formula:

wherein X is a covalent bond; and n is an integer from 1 to 30. Incertain embodiments, n is an integer from 1 to 10.

In certain embodiments, the compound of Formula I is selected from

-   (2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-3-(Cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;-   (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3    (cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one;-   (2    S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide;-   (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide;-   N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide;-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)    ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one;-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol;-   (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;    and-   (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)    piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,    and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared using techniquesknown to one of skill in the art. As disclosed herein, each compound ofFormula I comprises at least one —X-POLY group. The incorporation of the—X-POLY group into a compound of Formula I can be achieved by reacting asynthetic precursor/synthetic intermediate of a compound of Formula Iwith a POLY group having a functional group that is capable of reactingwith a functional group on the synthetic intermediate to compound ofFormula I. The synthetic intermediate of a compound of Formula I may incertain embodiments possess a group suitable for covalent attachment ofthe oligomer. Such groups include, but are not limited to, a freehydroxyl, carboxyl, carbonyl, thio, amino group, or the like. Suchgroups can be incorporated into the synthetic intermediate to provide apoint of attachment for the oligomer. As such, the oligomer can beincorporated at various stages of the synthesis, depending on thesynthetic scheme. The introduction and conversion of functional groupsin a synthetic intermediate are transformations that are generally knownto those of skill in the art and can be found in the relevant texts. Seee.g. M. Smith, March's Advanced Organic Chemistry: Reactions, Mechanismsand Structure, (7^(th) ed. 2013); Carey and Sundberg, Advanced OrganicChemistry, (5^(th) ed. 2007).

The group “X” adjacent to POLY in the compound of Formula I is typicallyformed by reaction of a functional group on a terminus of the oligomer(or one or more monomers when it is desired to “grow” the oligomer ontothe compound of the present invention) with a corresponding functionalgroup within synthetic precursor/intermediate to a compound of FormulaI. For example, an amino group on an oligomer may be reacted with acarboxylic acid or an activated carboxylic acid derivative on theintermediate, or vice versa, to produce an amide linkage. Alternatively,reaction of an amine on an oligomer with an activated carbonate (e.g.succinimidyl or benzotriazyl carbonate) on the intermediate, or viceversa, forms a carbamate linkage. Reaction of an amine on an oligomerwith an isocyanate (R—N═C═O) on an intermediate, or vice versa, forms aurea linkage (R—NH—(C═O)—NH—R′). Further, reaction of an alcohol(alkoxide) group on an oligomer with an alkyl halide, or halide groupwithin an intermediate, or vice versa, forms an ether linkage. In yetanother approach, an intermediate having an aldehyde function is coupledto an oligomer amino group by reductive amination, resulting information of a secondary amine linkage between the oligomer and thecompound (or intermediate thereof) of the present invention.

Accordingly, each “POLY” (oligomer) is composed of up to three differentmonomer types selected from the group consisting of: alkylene oxide,such as ethylene oxide or propylene oxide; olefinic alcohol, such asvinyl alcohol, 1-propenol or 2-propenol; vinyl pyrrolidone; hydroxyalkylmethacrylamide or hydroxyalkyl methacrylate, where in certainembodiments, alkyl is methyl; α-hydroxy acid, such as lactic acid orglycolic acid; phosphazene, oxazoline, amino acids, carbohydrates suchas monosaccharides, saccharide or mannitol; and N-acryloylmorpholine. Incertain embodiments, monomer types include alkylene oxide, olefinicalcohol, hydroxyalkyl methacrylamide or methacrylate,N-acryloylmorpholine, and α-hydroxy acid. In certain embodiments, eacholigomer is, independently, a co-oligomer of two monomer types selectedfrom this group, or, in certain embodiments, is a homo-oligomer of onemonomer type selected from this group.

The two monomer types in a co-oligomer may be of the same monomer type,for example, two alkylene oxides, such as ethylene oxide and propyleneoxide. In certain embodiments, the oligomer is a homo-oligomer ofethylene oxide. Usually, although not necessarily, the terminus (ortermini) of the oligomer that is not covalently attached to a compound(or intermediate thereof) of the present invention is capped to renderit unreactive. Alternatively, the terminus may include a reactive group.When the terminus is a reactive group, the reactive group is eitherselected such that it is unreactive under the conditions of formation ofthe final oligomer or during covalent attachment of the oligomer to acompound (or intermediate thereof) of the present invention, or it isprotected as necessary. One common end-functional group is hydroxyl or—OH, particularly for oligoethylene oxides.

The water-soluble oligomer (e.g., “POLY” in the structures providedherein) can have any of a number of different geometries. For example,it can be linear, branched, or forked. Most typically, the water-solubleoligomer is linear or is branched, for example, having one branch point.Although much of the discussion herein is focused upon poly(ethyleneoxide) as an illustrative oligomer, the discussion and structurespresented herein can be readily extended to encompass any of thewater-soluble oligomers described above.

The molecular weight of the water-soluble oligomer, excluding the linkerportion, in certain embodiments is generally relatively low. Forexample, the molecular weight of the water-soluble oligomer is typicallybelow about 2200 Daltons, and more typically at around 1500 Daltons orbelow. In certain other embodiments, the molecular weight of thewater-soluble oligomer may be below 800 Daltons.

In certain embodiments, exemplary values of the molecular weight of thewater-soluble oligomer include less than or equal to about 500 Daltons,or less than or equal to about 420 Daltons, or less than or equal toabout 370 Daltons, or less than or equal to about 370 Daltons, or lessthan or equal to about 325 Daltons, less than or equal to about 280Daltons, less than or equal to about 235 Daltons, or less than or equalto about 200 Daltons, less than or equal to about 175 Daltons, or lessthan or equal to about 150 Daltons, or less than or equal to about 135Daltons, less than or equal to about 90 Daltons, or less than or equalto about 60 Daltons, or even less than or equal to about 45 Daltons.

In certain embodiments, exemplary values of the molecular weight of thewater-soluble oligomer, excluding the linker portion, include: belowabout 1500 Daltons; below about 1450 Daltons; below about 1400 Daltons;below about 1350 Daltons; below about 1300 Daltons; below about 1250Daltons; below about 1200 Daltons; below about 1150 Daltons; below about1100 Daltons; below about 1050 Daltons; below about 1000 Daltons; belowabout 950 Daltons; below about 900 Daltons; below about 850 Daltons;below about 800 Daltons; below about 750 Daltons; below about 700Daltons; below about 650 Daltons; below about 600 Daltons; below about550 Daltons; below about 500 Daltons; below about 450 Daltons; belowabout 400 Daltons; and below about 350 Daltons; but in each case aboveabout 250 Daltons.

In certain embodiments, the number of monomers in the water-solubleoligomer falls within one or more of the following inclusive ranges:between 1 and 30 (i.e., is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, and 30); between 1 and 25 (i.e., is selected from 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and25); between 1 and 20 (i.e., is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20); between 1 and 15 (isselected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15);between 1 and 10 (i.e., is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and10); between 10 and 25 (i.e., is selected from 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, and 25); and between 15 and 20(i.e., is selected from 15, 16, 17, 18, 19, and 20). In certaininstances, the number of monomers in series in the oligomer (and thecorresponding compound) is one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. Thus, forexample, when the water-soluble oligomer includes CH₃—(OCH₂CH₂)_(n)—,“n” is an integer that can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In certainembodiments, the number of monomers in the water-soluble oligomer fallswithin one or more of the following inclusive ranges: between 1 and 5(i.e., is selected from 1, 2, 3, 4, and 5); between 1 and 4 (i.e., canbe 1, 2, 3, or 4); between 1 and 3 (i.e., selected from 1, 2, or 3);between 1 and 2 (i.e., can be 1 or 2); between 2 and 5 (i.e., can beselected from 2, 3, 4, and 5); between 2 and 4 (i.e., is selected from2, 3, and 4); between 2 and 3 (i.e., is either 2 or 3); between 3 and 5(i.e., is either 3, 4 or 5); between 3 and 4 (i.e., is 3 or 4); andbetween 4 and 5 (i.e., is 4 or 5). In a specific instance, the number ofmonomers in series in the oligomer (and the corresponding compound) isselected from 1, 2, 3, 4, or 5. Thus, for example, when thewater-soluble oligomer includes CH₃—(OCH₂CH₂)_(n)—, “n” is an integerthat can be 1, 2, 3, 4, or 5.

When the water-soluble oligomer is attached to the syntheticintermediate of a compound of Formula I (in contrast to the step-wiseaddition of one or more monomers to effectively “grow” the oligomer ontothe compound of Formula I or synthetic intermediate thereof), thecomposition containing an activated form of the water-soluble oligomermay be monodispersed. In those instances, however, where a bimodalcomposition is employed, the composition will possess a bimodaldistribution centering around any two of the above numbers of monomers.Ideally, the polydispersity index of each peak in the bimodaldistribution, Mw/Mn, is 1.01 or less, and in certain embodiments, is1.001 or less, and in certain embodiments is 1.0005 or less. In certainembodiments, each peak possesses a MW/Mn value of 1.0000. For instance,a bimodal oligomer may have any one of the following exemplarycombinations of monomer subunits: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8,1-9, 1-10, and so forth; 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, and soforth; 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, and so forth; 4-5, 4-6, 4-7,4-8, 4-9, 4-10, and so forth; 5-6, 5-7, 5-8, 5-9, 5-10, and so forth;6-7, 6-8, 6-9, 6-10, and so forth; 7-8, 7-9, 7-10, and so forth; and8-9, 8-10, and so forth.

In some instances, the composition containing an activated form of thewater-soluble oligomer will be trimodal or even tetramodal, possessing arange of monomers units as previously described. Oligomer compositionspossessing a well-defined mixture of oligomers (i.e., being bimodal,trimodal, tetramodal, and so forth) can be prepared by mixing purifiedmonodisperse oligomers to obtain a desired profile of oligomers (amixture of two oligomers differing only in the number of monomers isbimodal; a mixture of three oligomers differing only in the number ofmonomers is trimodal; a mixture of four oligomers differing only in thenumber of monomers is tetramodal), or alternatively, can be obtainedfrom column chromatography of a polydisperse oligomer by recovering the“center cut”, to obtain a mixture of oligomers in a desired and definedmolecular weight range.

In certain embodiment, the water-soluble oligomer is obtained from acomposition that is unimolecular or monodisperse. That is, the oligomersin the composition possess the same discrete molecular weight valuerather than a distribution of molecular weights. Some monodisperseoligomers can be purchased from commercial sources such as thoseavailable from Sigma-Aldrich, or alternatively, can be prepared directlyfrom commercially available starting materials such as Sigma-Aldrich.Water-soluble oligomers can be prepared as described in Chen and Baker,J. Org. Chem. 6870-6873 (1999), WO 02/098949, and U.S. PatentApplication Publication 2005/0136031.

As stated above, the water-soluble oligomer includes at least onefunctional group prior to reaction with the synthetic intermediate of acompound of Formula I. The functional group typically comprises anelectrophilic or nucleophilic group for covalent attachment to theintermediate, depending upon the reactive group contained within theintermediate. Examples of nucleophilic groups that may be present ineither the oligomer or the intermediate include hydroxyl, amine,hydrazine (—NHNH₂), hydrazide (—C(O)NHNH₂), and thiol. Preferrednucleophiles include amine, hydrazine, hydrazide, and thiol,particularly amine. Most intermediates will possess a free hydroxyl,amino, thio, aldehyde, ketone, or carboxyl group for reaction with thefunctional group on the oligomer.

Examples of electrophilic functional groups that may be present ineither the oligomer or the synthetic intermediate of a compound ofFormula I include carboxylic acid, carboxylic ester, particularly imideesters, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde,ketone, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone,maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, silane,alkoxysilane, and halosilane. More specific examples of these groupsinclude succinimidyl ester or carbonate, imidazoyl ester or carbonate,benzotriazole ester or carbonate, vinyl sulfone, chloroethylsulfone,vinylpyridine, pyridyl disulfide, iodoacetamide, glyoxal, dione,mesylate, tosylate, and tresylate (2,2,2-trifluoroethanesulfonate).

Also included are sulfur analogs of several of these groups, such asthione, thione hydrate, thioketal, is 2-thiazolidine thione, etc., aswell as hydrates or protected derivatives of any of the above moieties(e.g. aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal,ketal, thioketal, thioacetal).

It is possible, for example, to react a synthetic intermediate of acompound of Formula I bearing a carboxyl group by coupling it to anamino-terminated oligomeric ethylene glycol, to provide a syntheticintermediate for further modification or a compounds of Formula Iwherein X comprises an amide. This can be performed, for example, bycombining the carboxyl group-bearing intermediate with theamino-terminated oligomeric ethylene glycol in the presence of acoupling reagent, (such as dicyclohexylcarbodiimide or “DCC”) in ananhydrous organic solvent. Similarly, the above reaction may take placebetween a synthetic intermediate of a compound of Formula I bearing anamino group and a carboxyl-terminated oligomeric ethylene glycol.

Further, it is possible to react a synthetic intermediate of a compoundof Formula I bearing a hydroxyl group with an oligomeric ethylene glycolhalide to result in a synthetic intermediate for further modification ora compound of Formula I wherein X comprises an ether (—O—). This can beperformed, for example, by using sodium hydride to deprotonate thehydroxyl group followed by reaction with a halide-terminated oligomericethylene glycol. Similarly, the above reaction may take place between asynthetic intermediate of a compound of Formula I bearing a halo groupand an oligomeric ethylene glycol bearing a hydroxyl group.

In another example, it is possible to convert a ketone of a syntheticintermediate of a compound of Formula I bearing a ketone group to ahydroxyl group by first reducing the ketone group to form thecorresponding hydroxyl group. Thereafter, the synthetic intermediate maybe reacted now bearing a hydroxyl group may be reacted as describedherein.

In still another instance, it is possible to react a syntheticintermediate of a compound of Formula I bearing an amine group. In oneapproach, the amine group-bearing synthetic intermediate and acarbonyl-bearing oligomer are dissolved in a suitable buffer after whicha suitable reducing agent (e.g., NaCNBH₃) is added. Following reduction,the result is an amine linkage formed between the amine group of theamine group-containing synthetic intermediate and the carbonyl carbon ofthe aldehyde-bearing oligomer. Similarly, the reaction may take placewhere the synthetic intermediate bears a carbonyl group and the oligomerbears and amine.

In another approach for preparing a compound of the present invention,where the synthetic intermediate bears an amine group, a carboxylicacid-bearing oligomer and the amine group-bearing intermediate arecombined, typically in the presence of a coupling reagent (e.g., DCC).The result is an amide linkage formed between the amine group of theamine group-containing synthetic intermediate and the carbonyl of thecarboxylic acid-bearing oligomer. Similarly the above reaction may takeplace when the synthetic intermediate bears a carboxyl group and theoligomer bears an amine group.

As non-limiting examples, the synthetic examples below provide exemplarymeans for preparing compounds of the present invention. One of skill inthe art would understand such procedures may be modified depending onthe desired target compound or reaction conditions.

In certain embodiments, compounds of Formula I, including those ofFormula XVI and XVII, may be prepared according to the following scheme:

In this scheme, a compound of formula 1 is reacted with an aldehyde orketone under reductive amination conditions. The resulting compound 2 isfurther deprotected (submitted to O-demethylation conditions) to form afree hydroxyl containing compound. That compound is further subjected toreaction with a poly(ethylene glycol) coupling conditions for forming acompound of Formula I, including those of Formula XVI and XVII. It isunderstood that the reagents and conditions listed in this scheme areexemplary and substitutions could be made based on the desired targetcompound.

In certain embodiments, compounds of Formula I, including those ofFormula XV, may be prepared according to the following scheme:

In the above scheme, the compound of formula 1 is protected understandard protection conditions. The resulting compound of formula 2 iscoupled to a protected amino acid, under reductive amino acidconditions. The acid portion of the compound of formula 3 is deprotectedand reacted with a poly(ethylene glycol) reagent. Finally, the compoundof formula 5 is deprotected to provide the target compound of formula 6.One of skill in the art would appreciate that various other amino acidscould be substituted, depending on the desired product.

In certain embodiments, compounds of Formula I, including those ofFormula X, may be prepared according to the following scheme:

In the reaction scheme above, the compound of formula 1 is submitted toformylation conditions to prepare compound of formula 2. That compoundof formula 2 is reduced to the hydroxylated compound of formula 3. Asuitable leaving group may be introduced into the compound to formula 3,for example a halogen, to form a compound of formula 4. That compound offormula 4 may be reacted with a suitable poly(ethylene glycol) reagent(e.g. where X is O or N) to form a compound of formula 5. The targetcompound of formula 6 is prepared by deprotecting the compound offormula 6.

Certain compounds of the present invention are understood to haveactivity as agonists of the kappa opioid receptor. The compounds mayalso have activity as agonists of the mu opioid receptor. Further, thecompounds of the present invention may be mixed agonists of both thekappa and mu opioid receptor. The ability of each compound disclosedherein to act as kappa, mu, or mixed opioid agonists may be determinedusing methods known to those of skill in the art and as disclosedherein. The activity of compounds as kappa, mu, or mixed agonists can beassessed with in-vitro binding and functional assays in kappa opioidreceptor and/or mu opioid receptor expressing cell lines/membranes andcompared to known kappa/mu agonists.

Approaches for evaluating analgesic activity of a compound of thepresent invention in vivo include a “writhing test.” Briefly, thecompound to be tested is administered [by, for example, injection (e.g.,subcutaneous injection)] to the mouse. Thereafter, a 0.5% acetic acidsolution is administered (i.p.) to a mouse and the numbers of writhingresponses are counted for twenty minutes. Antinociception is quantifiedas reduction in the number of writhes respective to vehicle.

Beyond acting as kappa, mu, and/or mixed opioid agonists, the presentcompounds are intended to act primarily on opioid receptors in theperipheral nervous system rather than those receptors in the centralnervous system. As recited above, each compound of Formula I includes atleast one —X-POLY group. It is believed that the POLY portion of thecompound of Formula I acts to reduce the rate and/or extent to which thecompound of Formula I crosses into the central nervous system. Thepropensity of a compound of the present invention to cross theblood-brain barrier may be measured by methods known to those of skillin the art and those described herein.

With respect to the blood-brain barrier (“BBB”), this barrier consistsof a continuous layer of unique endothelial cells joined by tightjunctions. The cerebral capillaries, which comprise more than 95% of thetotal surface area of the BBB, represent the principal route for theentry of most solutes and drugs into the central nervous system.

As will be understood by one of skill in the art, molecular size,lipophilicity, and P-glycoprotein (“PgP”) interaction are among theprimary parameters affecting the intrinsic BBB permeability propertiesof a given molecule. That is to say, these factors, when taken incombination, play a significant role in determining whether a givenmolecule passes through the BBB. Other factors (e.g., other activetransport mechanisms) may also play a role in ultimately determiningwhether a given molecule will pass through the BBB.

With respect to molecular size, the molecular size plays a significantrole in determining whether a given molecule will pass through the BBB.Relatively very large molecules, for example a molecule having amolecular weight of 5,000 Daltons, will not cross the BBB, whereasrelatively small molecules are more likely to cross the BBB. Otherfactors, however, also play a role in BBB crossing. Antipyrine andatenolol are both small molecule drugs; antipyrine readily crosses theBBB, whereas passage of atenolol is very limited, or effectivelynon-existent. Antipyrine is an industry standard for a high BBBpermeation; atenolol is an industry standard for low permeation of theBBB. See, e.g., Summerfield et al., J Pharmacol Exp Ther 322:205-213(2007).

Lipophilicity is also a factor in BBB permeation. Lipophilicity may beexpressed as log P (partition coefficient) or in some instances log D(distribution coefficient). The log P (or log D) for a given moleculecan be readily assessed by one of skill in the art. The value for log Pmay be a negative number (more hydrophilic molecules) or a positivenumber (more hydrophobic molecules). As used herein when referring tolog P, “more negative” means moving in the direction, on the log Pscale, from positive to negative log P (e.g., a log P of 2.0 is “morenegative” than a log P of 4.0, a log P of −2.0 is “more negative” than alog P of −1.0). Molecules having a negative log P (hydrophilicmolecules) generally do not permeate the BBB.

Permeability across the BBB is also dependent on the influence oftransporters, such as P-glycoprotein, or PgP, an ATP-dependent effluxtransporter highly expressed at the BBB. One of skill in the art canreadily determine whether a compound is a substrate for PgP using invitro methods. Compounds which are substrates for PgP in vitro likelywill not permeate the BBB in vivo. Conversely, poor substrates for PgP,as assessed in vitro, are generally likely to display in vivopermeability of the BBB, provided the compound meets other criteria asdiscussed herein and as known to one of skill in the art. See, e.g.,Tsuji, NeuroRx 2:54-62 (2005) and Rubin and Staddon, Annu. Rev.Neurosci. 22:11-28 (1999).

Even in the context of multiple variables (e.g., molecular size,lipophilicity, transporter influences, linkage type), it is possible toanalyze a particular compounds ability to cross the BBB using methodsknown to those of skill in the art.

For any given compound whose degree of BBB crossing ability is notreadily known, such BBB crossing ability can be determined using asuitable animal model such as an in situ rat brain perfusion (“RBP”)model. Briefly, the RBP technique involves cannulation of the carotidartery followed by perfusion with a compound solution under controlledconditions, followed by a wash out phase to remove compound remaining inthe vascular space. More specifically, in the RBP model, a cannula isplaced in the left carotid artery and the side branches are tied off. Aphysiologic buffer containing the analyte (typically but not necessarilyat a 5 micromolar concentration level) is perfused at a flow rate ofabout 10 mL/minute in a single pass perfusion experiment. After 30seconds, the perfusion is stopped and the brain vascular contents arewashed out with compound-free buffer for an additional 30 seconds. Thebrain tissue is then removed and analyzed for compound concentrationsvia liquid chromatograph with tandem mass spectrometry detection(LC/MS/MS). Alternatively, blood-brain barrier permeability can beestimated based upon a calculation of the compound's molecular polarsurface area (“PSA”), which is defined as the sum of surfacecontributions of polar atoms (usually oxygens, nitrogens and attachedhydrogens) in a molecule. The PSA has been shown to correlate withcompound transport properties such as blood-brain barrier transport.Methods for determining a compound's PSA can be found, e.g., in, Ertl etal. (2000) J. Med. Chem. 43:3714-3717 and Kelder et al. (1999) Pharm.Res. 16:1514-1519.

The compounds of the present invention are expected to have varyingdegrees of activity against opioid receptors as well as varying degreesto which they cross the BBB. While the compounds of the presentinvention have activity against the kappa and/or mu opioid receptor,they are believed to also have some degree of exclusion from the centralnervous system based on the presence of the X-POLY group in eachcompound.

Brain PK studies may also be conducted to measure the extent of brainentry in-vivo drug concentrations at enter the CNS at various timepost-dose. In brief, rodents are administered with the test article(oral, subcutaneous, or other). At various times post dose terminalblood is collected. Then the rodent is transcardially perfused with coldisotonic saline to remove as much blood from the tissues and brain areextracted. Both plasma and brain are measured for drug content withLC/MS/MS.

The locomotor activity (LMA) model may be conducted to measure changesin activity following test article administration, which may be used toassess the CNS effects of the drug. In brief, at a predetermined timepost-dose, rats are placed into observation chambers which are equippedwith infrared photocells that can sense motion in the x, y, and zplanes. Activity is measured as the number of photobeam breaks in agiven plane (horizontal or vertical) or total distance traveled.

In further embodiments, the invention provides for compositionscomprising the compounds disclosed herein and a pharmaceuticallyacceptable excipient or carrier. Generally, the compound itself will bein a solid form (e.g., a precipitate), which can be combined with asuitable pharmaceutical excipient that can be in either solid or liquidform.

Exemplary excipients include, without limitation, those selected fromthe group consisting of carbohydrates, inorganic salts, antimicrobialagents, antioxidants, surfactants, buffers, acids, bases, andcombinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The preparation may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe compound or other components of the preparation. Suitableantioxidants for use in the present invention include, for example,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, andcombinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines (althoughpreferably not in liposomal form), fatty acids and fatty esters;steroids, such as cholesterol; and chelating agents, such as EDTA, zincand other such suitable cations.

Pharmaceutically acceptable acids or bases may be present as anexcipient in the preparation. Nonlimiting examples of acids that can beused include those acids selected from the group consisting ofhydrochloric acid, acetic acid, phosphoric acid, citric acid, malicacid, lactic acid, formic acid, trichloroacetic acid, nitric acid,perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, andcombinations thereof. Examples of suitable bases include, withoutlimitation, bases selected from the group consisting of sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and combinations thereof.

The amount of the compound in the composition will vary depending on anumber of factors, but will optimally be a therapeutically effectivedose when the composition is stored in a unit dose container. Atherapeutically effective dose can be determined experimentally byrepeated administration of increasing amounts of the compound in orderto determine which amount produces a clinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, in certain embodimentsfrom about 5%-98% by weight, in certain embodiments from about 15-95% byweight of the excipient, and in certain embodiments concentrations lessthan 30% by weight.

These foregoing pharmaceutical excipients along with other excipientsand general teachings regarding pharmaceutical compositions aredescribed in “Remington: The Science & Practice of Pharmacy”, 19^(th)ed., Williams & Williams, (1995), the “Physician's Desk Reference”,52^(nd) ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H.,Handbook of Pharmaceutical Excipients, 3^(rd) Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

The pharmaceutical compositions can take any number of forms and theinvention is not limited in this regard. In certain embodiments,preparations are in a form suitable for oral administration such as atablet, caplet, capsule, gel cap, troche, dispersion, suspension,solution, elixir, syrup, lozenge, transdermal patch, spray, suppository,and powder. Oral dosage forms are preferred for those compounds that areorally active, and include tablets, caplets, capsules, gel caps,suspensions, solutions, elixirs, and syrups, and can also comprise aplurality of granules, beads, powders or pellets that are optionallyencapsulated. Such dosage forms are prepared using conventional methodsknown to those in the field of pharmaceutical formulation and describedin the pertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques are preferred when preparing tablets or capletscontaining the compounds described herein. In addition to the compound,the tablets and caplets will generally contain inactive,pharmaceutically acceptable carrier materials such as binders,lubricants, disintegrants, fillers, stabilizers, surfactants, coloringagents, and the like. Binders are used to impart cohesive qualities to atablet, and thus ensure that the tablet remains intact. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone,cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, and the like), and Veegum. Lubricantsare used to facilitate tablet manufacture, promoting powder flow andpreventing particle capping (i.e., particle breakage) when pressure isrelieved. Useful lubricants are magnesium stearate, calcium stearate,and stearic acid. Disintegrants are used to facilitate disintegration ofthe tablet, and are generally starches, clays, celluloses, algins, gums,or crosslinked polymers. Fillers include, for example, materials such assilicon dioxide, titanium dioxide, alumina, talc, kaolin, powderedcellulose, and microcrystalline cellulose, as well as soluble materialssuch as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

Capsules are also preferred oral dosage forms, in which case thecompound-containing composition can be encapsulated in the form of aliquid or gel (e.g., in the case of a gel cap) or solid (includingparticulates such as granules, beads, powders or pellets). Suitablecapsules include hard and soft capsules, and are generally made ofgelatin, starch, or a cellulosic material. Two-piece hard gelatincapsules are preferably sealed, such as with gelatin bands or the like.

Included are parenteral formulations in the substantially dry form(typically as a lyophilizate or precipitate, which can be in the form ofa powder or cake), as well as formulations prepared for injection, whichare typically liquid and requires the step of reconstituting the dryform of parenteral formulation. Examples of suitable diluents forreconstituting solid compositions prior to injection includebacteriostatic water for injection, dextrose 5% in water,phosphate-buffered saline, Ringer's solution, saline, sterile water,deionized water, and combinations thereof.

In some cases, compositions intended for parenteral administration cantake the form of nonaqueous solutions, suspensions, or emulsions, eachtypically being sterile. Examples of nonaqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils, such as olive oiland corn oil, gelatin, and injectable organic esters such as ethyloleate.

The parenteral formulations described herein can also contain adjuvantssuch as preserving, wetting, emulsifying, and dispersing agents. Theformulations are rendered sterile by incorporation of a sterilizingagent, filtration through a bacteria-retaining filter, irradiation, orheat.

The compound can also be administered through the skin usingconventional transdermal patch or other transdermal delivery system,wherein the compound is contained within a laminated structure thatserves as a drug delivery device to be affixed to the skin. In such astructure, the compound is contained in a layer, or “reservoir,”underlying an upper backing layer. The laminated structure can contain asingle reservoir, or it can contain multiple reservoirs.

The compound can also be formulated into a suppository for rectaladministration. With respect to suppositories, the compound is mixedwith a suppository base material which is (e.g., an excipient thatremains solid at room temperature but softens, melts or dissolves atbody temperature) such as coca butter (theobroma oil), polyethyleneglycols, glycerinated gelatin, fatty acids, and combinations thereof.Suppositories can be prepared by, for example, performing the followingsteps (not necessarily in the order presented): melting the suppositorybase material to form a melt; incorporating the compound (either beforeor after melting of the suppository base material); pouring the meltinto a mold; cooling the melt (e.g., placing the melt-containing mold ina room temperature environment) to thereby form suppositories; andremoving the suppositories from the mold.

The invention also provides a method for administering a compoundprovided herein to a patient suffering from a condition that isresponsive to treatment with the compound such as pain. The methodcomprises administering, generally orally, a therapeutically effectiveamount of the compound (in certain embodiments provided as part of apharmaceutical preparation). Other modes of administration are alsocontemplated, such as pulmonary, nasal, buccal, rectal, sublingual,transdermal, and parenteral. As used herein, the term “parenteral”includes subcutaneous, intravenous, intra-arterial, intraperitoneal,intracardiac, intrathecal, and intramuscular injection, as well asinfusion injections.

The method of administering may be used to treat any condition that canbe remedied or prevented by administration of a kappa opioid agonist, amu opioid agonist, or a mixed opioid agonist. Most commonly, thecompounds provided herein are administered for the management of pain,including visceral pain, chronic pelvic pain and interstitial cystitis.Kappa agonists have also been used to treat irritable bowel syndrome.Those of ordinary skill in the art appreciate which conditions aspecific compound can effectively treat. The actual dose to beadministered will vary depend upon the age, weight, and generalcondition of the subject as well as the severity of the condition beingtreated, the judgment of the health care professional, and compoundbeing administered. Therapeutically effective amounts are known to thoseskilled in the art and/or are described in the pertinent reference textsand literature. Generally, a therapeutically effective amount will rangefrom about 0.001 mg to 1000 mg, in certain embodiments in doses from0.01 mg/day to 750 mg/day, and in certain embodiments in doses from 0.10mg/day to 500 mg/day.

The unit dosage of any given compound (in certain embodiments, providedas part of a pharmaceutical preparation) can be administered in avariety of dosing schedules depending on the judgment of the clinician,needs of the patient, and so forth. The specific dosing schedule will beknown by those of ordinary skill in the art or can be determinedexperimentally using routine methods. Exemplary dosing schedulesinclude, without limitation, administration five times a day, four timesa day, three times a day, twice daily, once daily, three times weekly,twice weekly, once weekly, twice monthly, once monthly, and anycombination thereof. Once the clinical endpoint has been achieved,dosing of the composition is halted.

All articles, books, patents, patent publications and other publicationsreferenced herein are hereby incorporated by reference in theirentireties.

It is to be understood that while the invention has been described inconjunction with certain and specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLES

All chemical reagents referred to in the appended examples arecommercially available unless otherwise indicated. The preparation ofPEG-mers is described in, for example, U.S. Patent ApplicationPublication No. 2005/0136031.

Example 1 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(1)

(2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(1) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonate

Ketazocine (0.50 g, 1.75 mmol) was dissolved in anhydrousdichloromethane (40 mL) and triethylamine (1.24 mL, 8.76 mmol). Thelight-yellow solution was cooled to 0° C. and addedN-phenyl-bis(trifluoromethanesulfonimide) (0.94 g, 2.63 mmol). Theyellow reaction mixture was allowed to equilibrate to room temperature.After approximately 17 hours the reaction mixture was diluted withdichloromethane (50 mL). The mixture was transferred to a separatoryfunnel and washed with water (40 mL), IN sodium hydroxide (40 mL) andsaturated sodium chloride (40 mL). The organic portion was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified on a column of silica gel using dichloromethane/methanol (9:1)as eluent to give(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonate (0.64 g, 88%) as a yellow oil. ¹H NMR (500MHz, CDCl₃): δ 8.09 (m, 1H), 7.22 (m, 2H), 3.32 (m, 1H), 2.93 (m, 1H),2.67 (m, 1H), 2.23 (m, 1H), 2.09 (m, 1H), 2.01 (m, 2H), 1.95 (m, 1H),1.53 (m, 1H), 1.50 (s, 3H), 0.87 (m, 2H), 0.50 (m, 2H), 0.07 (m, 1H),0.05 (m, 1H); MS (EI) for C₁₉H₂₂F₃NO₄S: 418 (MH⁺).

Step 2: Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(1)

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonate (33 mg, 0.079 mmol) from step 1,2-[2-(2-methoxyethoxy)ethoxy]ethanamine (40 mg, 0.24 mmol) and1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial,and then heated under microwave irradiation for 2 hours at 200° C. Thereaction mixture was cooled to room temperature, poured into 12 mL waterand extracted with methyl tert-butyl ether (3×5 mL). The combinedorganic portions were washed with water (20 mL) and saturated sodiumchloride (20 mL) and then dried over anhydrous sodium sulfate. Theresidue was purified by silica gel chromatography usingmethanol/dichloromethane (1:9) as eluent to give 0.012 g (35%) of(2S,6R,11R)-3-(cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(1) as a yellow oil. ¹H NMR (500 MHz, CDCl₃): 7.85 (s, 1H), 6.50 (m,1H), 6.39 (s, 1H), 4.84 (m, 1H), 3.74 (m, 2H), 3.72 (m, 6H), 3.66 (m,2H), 3.37 (m, 5H), 2.91 (m, 1H), 2.76 (m, 1H), 2.12 (m, 2H), 2.01 (m,3H), 1.52 (m, 1H), 1.31 (m, 3H), 0.89 (m, 4H), 0.47 (m, 2H), 0.25 (m,1H), 0.05 (m, 1H); MS (EI) for C₂₅H₃₈N₂O₄: 431 (MH⁺).

Example 2 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(2)

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonate (0.10 g, 0.24 mmol) (from Example 1, step 1),2,5,8,11,14-pentaoxahexadecan-16-amine (0.18 g, 0.73 mmol) and1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial,and then heated under microwave irradiation for 2 hours at 200° C. Thereaction mixture was cooled to room temperature, poured into 12 mL waterand extracted with methyl tert-butyl ether (3×5 mL). The combinedorganic portions were washed with water (20 mL) and saturated sodiumchloride (20 mL) and then dried over anhydrous sodium sulfate. Theresidue was purified by silica gel chromatography usingmethanol/dichloromethane (1:9) as eluent to give 0.012 g (35%) of(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-oneas a yellow oil. ¹H NMR (500 MHz, CDCl3): 7.85 (m, 1H), 6.48 (m, 1H),6.39 (m, 1H), 4.92 (m, 1H), 3.72 (m, 2H), 3.63 (m, 15H), 3.55 (m, 2H),3.37 (m, 5H), 2.90 (m, 1H), 2.74 (m, 1H), 2.12-1.95 (m, 4H), 1.51 (m,1H), 1.38 (s, 3H), 0.89 (m, 4H), 0.47 (m, 2H), 0.25 (m, 1H), 0.05 (m,1H); MS (EI) for C₂₉H₄₆N₂O₆: 519 (MH⁺).

Example 3 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(3)

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonate (0.10 g, 0.24 mmol) (from Example 1, step 1),2,5,8,11,14,17,20-heptaoxadocosan-22-amine (0.18 g, 0.73 mmol) and1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial,and then heated under microwave irradiation for 2 hours at 200° C. Thereaction mixture was cooled to room temperature, poured into 12 mL waterand extracted with methyl tert-butyl ether (3×5 mL). The combinedorganic portions were washed with water (20 mL) and saturated sodiumchloride (20 mL) and then dried over anhydrous sodium sulfate. Theresidue was purified by silica gel chromatography usingmethanol/dichloromethane (1:9) as eluent to give 0.08 g (55%) of(2S,6R,11R)-3-(cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-oneas a yellow oil. ¹H NMR (500 MHz, CDCl3): 7.85 (m, 1H), 6.49 (m, 1H),6.38 (m, 1H), 3.73 (m, 2H), 3.72 (m, 24H), 3.71 (m, 2H), 3.54 (m, 5H),2.97 (m, 1H), 2.75 (m, 1H), 2.15 (m, 1H), 2.01 (m, 3H), 1.49 (m, 1H),1.38 (s, 3H), 0.89 (m, 3H), 0.48 (m, 2H), 0.46 (m, 2H), 0.25 (m, 1H); MS(EI) for C₃₃H₅₄N₂O₈: 607 (MH⁺).

Example 4 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(4)

Into a three-necked flask was placed ketazocine (0.47 g, 1.66 mmol),potassium carbonate (0.57 g, 4.16 mmol),2-[2-(2-methoxyethoxy)ethoxy]ethyl methanesulfonate (0.44 g, 1.83 mmol)in acetone (35 mL). The yellow reaction mixture was heated to reflux andstirred under nitrogen. After approximately 17 hours reflux the yellowmixture was cooled to room temperature. The solvent was removed underreduced pressure and the residue partitioned between water anddichloromethane (25 mL each). The aqueous layer was extracted withdichloromethane (3×12 mL). The combined organic portions were washedwith water and saturated sodium chloride (2×25 mL each). The organicportion was filtered and concentrated and the residue was purified on acolumn of silica gel using dichloromethane/methanol (9:1) as eluent togive(2S,6R,11R)-3-(cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(64 mg, 37% yield), as a light-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ7.80 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), 4.19 (m, 2H), 3.75 (m, 2H),3.75 (m, 2H), 3.58-3.42 (m, 8H), 3.33 (s, 3H), 3.13 (m, 1H), 2.77 (m,1H), 2.47 (m, 2H), 2.05-1.85 (m, 4H), 1.45 (m, 1H), 1.38 (s, 3H), 0.85(m, 1H0, 0.77 (m, 3H), 0.42 (m, 2H), 0.19 (m, 1H); MS (EI) forC₂₅H₃₇NO₅: 432 (MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding IN hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as a white powder.

Example 5 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(5)

Into a three-necked flask was placed ketazocine (0.10 g, 0.35 mmol),potassium carbonate (0.12 g, 0.87 mmol),2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate (0.12 g, 0.38 mmol)in acetone (12 mL). The yellow reaction mixture was heated to reflux andstirred under nitrogen. After approximately 17 hours reflux the yellowmixture was cooled to room temperature. The solvent was removed underreduced pressure and the residue partitioned between water anddichloromethane (10 mL each). The aqueous layer was extracted withdichloromethane (3×8 mL). The combined organic portions were washed withwater and saturated sodium chloride (2×15 mL each). The organic portionwas filtered and concentrated and the residue was purified on a columnof silica gel using dichloromethane/methanol (9:1) as eluent to give(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(0.11 g, 63% yield), as a light-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ7.95 (m, 1H), 6.82 (m, 2H), 4.19 (m, 2H), 3.81 (m, 2H), 3.75-3.56 (m,16H), 3.34 (s, 3H), 3.25 (m, 1H), 2.92 (m, 1H), 2.71 (m, 1H), 2.18 (m,1H), 1.94 (m, 3H), 1.50 (m, 1H), 1.40 (s, 3H), 0.88 (m, 4H), 0.49 (m,2H), 0.30 (m, 1H), 0.10 (m, 1H); MS (EI) for C₂₉H₄₅NO₇: 520 (MH⁺).

Example 6 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(6)

Into a three-necked flask was placed ketazocine (0.10 g, 0.35 mmol),potassium carbonate (0.12 g, 0.87 mmol),2,5,8,11,14,17,20-heptaoxadocosan-22-yl methanesulfonate (0.15 g, 0.36mmol) in acetone (10 mL). The yellow reaction mixture was heated toreflux and stirred under nitrogen. After approximately 17 hours refluxthe yellow mixture was cooled to room temperature. The solvent wasremoved under reduced pressure and the residue partitioned between waterand dichloromethane (10 mL each). The aqueous layer was extracted withdichloromethane (3×8 mL). The combined organic portions were washed withwater and saturated sodium chloride (2×15 mL each). The organic portionwas filtered and concentrated and the residue was purified on a columnof silica gel using dichloromethane/methanol (9:1) as eluent to give(2S,6R,11R)-3-(cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one(0.12 g, 57% yield), as a light-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ7.95 (m, 1H), 6.84-6.81 (m, 2H), 4.18 (m, 2H), 3.87 (m, 2H), 3.73-3.52(m, 24H), 3.38 (s, 3H), 3.24 (m, 1H), 2.92 (m, 1H), 2.71 (m, 1H), 2.15(m, 1H), 1.98 (m, 3H), 1.52 (m, 1H), 1.41 (s, 3H), 0.86 (m, 4H), 0.47(m, 2H), 0.26 (m, 1H), 0.06 (m, 1H); MS (EI) for C₃₃H₅₃NO₉: 608 (MH⁺).

Example 7 Preparation of(2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(7)

(2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(7) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (2-hydroxyphenyl)carbamate

2-Amino phenol (6 g, 55 mmol) was dissolved in 60 mL of THF. (Boc)₂O (12g, 55 mmol) was added to the above mixture and stirred for 16 h. Themixture was concentrated under vacuum to get a gummy mass. Gummy masswas precipitated using 20% MTBE/Hexane. Precipitated solid was filteredand washed with hexane to afford tert-butyl (2-hydroxyphenyl)carbamate(11.2 g, 97% yield)

Step 2: Preparation of tert-butyl(2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate

tert-Butyl (2-hydroxyphenyl)carbamate (3 g, 14.34 mmol), mPEG₅-OMs (5.21g, 15.77 mmol) and K₂CO₃ (5.94 g. 43.0 mmol) were dissolved in 20 mL ofDMF. The mixture was heated to 80° C. and stirred at that temperaturefor 18 h. Reaction was cooled to 25° C. and concentrated under vacuum toget a gummy mass. The gummy residue was dissolved in 30 mL of water (10vol) and compound was extracted in EtOAc. Organic layer was washed with1M aq NaOH and brine sequentially, then dried over anhydrous sodiumsulfate & concentrated under vacuum to afford tert-butyl(2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate (22) (4 g, 63%yield) as a viscous liquid.

Step 3: Preparation of 2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

tert-Butyl (2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate (3.2g, 7.21 mmol) was dissolved in 25 mL of 4M HCl in IPA. The mixture wasstirred for 1 h and concentrated under vacuum. The residue was dissolvedin 50 mL of water and pH of the aqueous solution was adjusted to 9.0(using 1M aq. NaOH). Compound was extracted into ethyl acetate, driedover anhydrous sodium sulfate, concentrated under vacuum to obtain(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline as pale yellow gum (2 g,86% yield).

Step 4: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(500 mg, 1.75 mmol) and triethyl amine (1.23 mL, 8.76 mmol) weredissolved in 10 mL of dichloromethane. PhNTf₂ (925 mg, 18.75 mmol) wasadded to the above mixture and the reaction, stirred for 16 h. uponcompletion the reaction was concentrated, Crude thus obtained, waspurified (by column chromatography) to get(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(709 mg, 97% yield).

Step 5: Preparation of(2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(7)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(200 mg, 0.48 mmol) and (2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline(197 mg, 0.575 mmol) were dissolved in toluene. BINAP (89 mg, 0.144mmol), Pd₂(dba)₃ (88 mg, 0.096 mmol) & Cs₂CO₃ (219 mg, 0.671 mmol) wereadded to the above mixture and stirred under heating at 110° C. for 2 h.The mixture was cooled to room temperature and concentrated undervacuum. Crude was purified by column chromatography to get(2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(7) (163 mg, 56% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.9 (d, 1H),7.4-7.42 (m, 1H), 6.90-7.0 (m, 5H), 6.75 (m, 1H), 4.19 (t, 2H), 3.86 (t,2H), 3.67-3.71 (m, 2H), 3.60-3.65 (m, 12H), 3.51-3.53 (m, 2H), 3.36 (s,3H), 3.23 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m, 1H), 2.12-2.14 (m,1H), 1.97-2.08 (m, 3H), 1.39 (s, 3H), 1.25 (m, 1H), 0.88-0.91 (m, 4H),0.46-0.48 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.08 (m, 1H); MS (ESI) forC₃₅H₅₀N₂O₇: 611.3289 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 8 Preparation of(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(8)

(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(24) was prepared according to the following steps.

Step 1: Preparation of 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

was prepared using procedures similar to Example 7, steps 1-3, wherein3-amino phenol was used in place of 2-amino phenol in step 1. Theproduct, 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline was preparedas a yellow gum (2.5 g, 90% yield)

Step 2: Preparation of(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(8)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(prepared in a manner similar to Example 7, step 4) (200 mg, 0.48 mmol)and 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline) (197 mg, 0.575mmol) were dissolved in toluene. BINAP (89 mg, 0.144 mmol), Pd₂(dba)₃(88 mg, 0.096 mmol) & Cs₂CO₃ (219 mg, 0.671 mmol) were added to theabove mixture. The reaction mixture was heated to 110° C. & stirred for2 h. The mixture was cooled to room temperature and concentrated undervacuum. Crude was purified by column chromatography to yield(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(8) (200 mg, 68.3% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, 1H),7.2-7.24 (m, 1H), 6.92-6.94 (m, 1H), 6.83 (d, 1H), 6.74-6.78 (m, 2H),6.62-6.64 (m, 1H), 6.19 (s, 1H), 4.12 (t, 2H), 3.85 (t, 2H), 3.63-3.73(m, 14H), 3.53-3.55 (m, 2H), 3.36 (s, 3H), 3.23 (m, 1H), 2.91-2.94 (m,1H), 2.72-2.76 (m, 1H), 2.11-2.13 (m, 1H), 1.97-2.08 (m, 3H), 1.38 (s,3H), 1.25 (m, 1H), 0.89-0.91 (m, 4H), 0.46-0.49 (m, 2H), 0.25-0.27 (m,1H), 0.05-0.08 (m, 1H); MS (ESI) for C₃₅H₅₀N₂O₇: 611.3289 (MH⁺). Thefree base was dissolved in 4M hydrochloride in 2-propanol. The mixturewas concentrated to afford product as hydrochloride salt.

Example 9 Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(9)

(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-onehydrochloride (28) was prepared according to the following steps.

Step 1: 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

was prepared using procedures similar to Example 7, steps 1-3, wherein4-amino phenol was used in place of 2-amino phenol in step 1. Theproduct, 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline was isolatedas a yellow gum (2.35 g, 96% yield)

Step 2: Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(9)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(prepared in a manner similar to Example 7, step 4) (150 mg, 0.36 mmol)and 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline (148 mg, 0.431mmol) were dissolved in toluene. BINAP (67 mg, 0.108 mmol), Pd₂(dba)₃(66 mg, 0.072 mmol) & Cs₂CO₃ (328 mg, 1.00 mmol) were added to the abovemixture and heated (110° C.) for 2 h. The mixture was cooled to roomtemperature and concentrated under vacuum. Crude was purified by columnchromatography to afford(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(9) (180 mg, 61.5% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.85 (d, 1H),7.11-7.13 (m, 2H), 6.91-6.93 (m, 2H), 6.71-6.73 (m, 1H), 6.65 (m, 1H),5.94 (bs, 1H), 4.14 (t, 2H), 3.87 (t, 2H), 3.63-3.75 (m, 14H), 3.53-3.55(m, 2H), 3.37 (s, 3H), 3.22 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m,1H), 1.97-2.13 (m, 4H), 1.34 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 4H),0.46-0.48 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) forC₃₅H₅₀N₂O₇: 611.3289 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 10 Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(10)

(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(10) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (2-aminophenyl)carbamate

Benzene-1,2-diamine (10 g. 92.47 mmol) was dissolved in 200 mL ofdioxane/water (2:1 ratio) and stirred for 10 min. Boc anhydride (21.2mL, 92.47 mmol) was added to the above mixture and stirred for 5 h.Dioxane was distilled off and mixture was cooled to room temperature.Compound was extracted into MTBE, dried over anhydrous sodium sulfate,and conc. under vacuum to get tert-butyl (2-aminophenyl)carbamate (7)(12.1 g, 63% yield)

Step 2: Preparation of tert-butyl(2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)carbamate

tert-Butyl (2-aminophenyl)carbamate (3 g, 14.41 mmol), sodiumbicarbonate (1.45 g, 17.296 mmol) and sodium lauryl sulfate (70 mg,0.245 mmol) were mixed in 70 mL of water. The mixture was heated to 80°C. and to it was charged mPEG₅-OMs (5.71 g, 17.296 mmol). The mixturewas stirred under heating for 16 h and then cooled to room temperature.The cooled reaction mixture was extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate & conc. undervacuum. Crude was purified by column chromatography to yield tert-butyl(2-(2,5,8,11,14-pentaoxahexadecan-16 ylamino)phenyl) carbamate (2 g, 31%yield).

Step 3: Preparation ofN1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine

tert-Butyl (2-(2,5,8,11,14-pentaoxahexadecan-16 ylamino)phenyl)carbamate (2 g, 4.52 mmol) was dissolved in 25 mL of 4M HCl in IPA. Themixture was stirred for 1 h and concentrated under vacuum. The residuewas dissolved in 50 mL of water and pH was adjusted to 9.0 using 1M aq.NaOH. The Compound was extracted into ethyl acetate, the organic layerwas dried over anhydrous sodium sulfate, concentrated under vacuum toget N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine as darkbrown gum (1.22 g, 79% yield).

Step 4:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

was prepared in a manner similar to Example 7, step 4.

Step 5: Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6methanobenzo[d]azocin-1(2H)-one (10)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(100 mg, 0.24 mmol) andN1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine weredissolved in toluene. BINAP (44.7 mg, 0.0718 mmol), Pd₂dba₃ (43.86 mg,0.0479 mmol) & Cs₂CO₃ (109.25 mg, 0.3353 mmol) were added to the abovemixture and heated to 110° C. for 2 h. The mixture was cooled to roomtemperature and concentrated under vacuum. Crude was purified by flashchromatography to yield(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6methanobenzo[d]azocin-1(2H)-one (10) (93 mg, 63% yield). ¹H NMR (500MHz, CDCl₃): δ 7.83 (d, 1H), 7.12-7.18 (m, 2H), 6.70-6.75 (m, 2H),6.58-6.61 (m, 2H), 5.95 (s, 1H), 4.45 (bs, 1H), 3.63-3.68 (m, 2H),3.55-3.62 (m, 14H), 3.49-3.54 (m, 2H), 3.33 (m, 5H), 3.21 (m, 1H),2.9-2.94 (m, 1H), 2.72-2.76 (m, 1H), 1.96-2.15 (m, 3H), 1.41-1.44 (m,1H), 1.37 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 3H), 0.46-0.48 (m, 2H),0.25-0.27 (m, 1H), 0.07 (m, 2H); MS (ESI) for C₃₅H₅₁N₃O₆: 610.3262(MH⁺). The free base was dissolved in 4M hydrochloride in 2-propanol.The mixture was concentrated to afford product as hydrochloride salt.

Example 11 Preparation of(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(11)

(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(8) was prepared according to the following steps.

Step 1: Preparation ofN1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine

N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine was preparedin a manner similar to steps 1-3 of example 7, with the exception thatBenzene-1,3-diamine was used as the starting material in step 1 in orderto arrive at the present orientation on the phenyl ring to yieldN1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine, as a darkbrown gum (1.8 g, 94% yield)

Step 2: Preparation of(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(11)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(prepared in a manner similar to Example 7, Step 4) (200 mg, 0.479 mmol)and N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine (147.66mg, 0.431 mmol) were dissolved in toluene. DPPF (53.11 mg, 0.0958 mmol),Pd₂dba₃ (29.83 mg, 0.0325 mmol) & sodium tert-butoxide (55.24 mg, 0.575mmol) were added to the above mixture. The reaction mix was heated to110° C. and stirred at that temperature for 3 h. Thereafter the mixturewas cooled to room temperature and concentrated under vacuum. Crude waspurified by preparative HPLC; giving(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(11) (95 mg, 32% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, 1H), 7.12(t, 1H), 6.90-6.92 (m, 1H), 6.82 (d, 1H), 6.53-6.55 (m, 1H), 6.44-6.45(m, 1H), 6.35-6.37 (m, 1H), 6.19 (s, 1H), 4.3 (bs, 1H), 3.69-3.71 (t,2H), 3.62-3.65 (m, 14H), 3.53-3.55 (m, 2H), 3.36 (s, 3H), 3.28 (t, 2H),3.23 (m, 1H), 2.92-2.94 (m, 1H), 2.72-2.76 (m, 1H), 2.14-2.06 (m, 1H),1.93-2.10 (m, 3H), 1.49-1.51 (m, 1H), 1.37 (s, 3H), 1.25-1.29 (m, 1H),0.89-0.91 (m, 3H), 0.44-0.50 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.07 (m,1H); MS (ESI) for C₃₅H₅₁N₃O₆: 610.3419 (MH⁺). The free base wasdissolved in 4M hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 12 Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(12)

(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(12) was prepared according to the following steps.

Step 1: N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine

was prepared in a manner similar to steps 1-3 of Example 8, with theexception that benzene-1,4-diamine was used as the starting material instep 1 in order to arrive at the present orientation on the phenyl ringto arrive at N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamineas dark brown gum (3.1 g, 98% yield)

Step 2: Preparation of(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(12)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(prepared in a manner similar to Example 7, Step 4) (3.6 g, 8.62 mmol)and N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine (2.95 g,8.62 mmol) were dissolved in toluene. BINAP (1.61 g, 2.58 mmol), Pd₂dba₃(1.58 g, 1.72 mmol) & Cs₂CO₃ (3.93 g, 8.62 mmol) were added to the abovemixture. The reaction mixture was heated to 110° C. and was stirred for2 h. The mixture was cooled to room temperature and concentrated undervacuum. Crude was purified by flash chromatography to yield(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(12) (1.7 g, 33.7% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.83 (d, 1H), 7.03(d, 2H), 6.64-6.66 (m, 3H), 6.82 (d, 1H), 5.87 (s, 1H), 4.18 (bs, 1H),3.72-3.74 (t, 2H), 3.63-3.67 (m, 14H), 3.53-3.55 (m, 2H), 3.37 (s, 3H),3.30 (t, 2H), 3.21 (m, 1H), 2.88-2.96 (m, 1H), 2.72-2.76 (m, 1H),1.93-2.10 (m, 4H), 1.48-1.50 (m, 1H), 1.37 (s, 3H), 1.25 (m, 1H),0.88-0.90 (m, 3H), 0.44-0.50 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.07 (m,1H); MS (ESI) for C₃₅H₅₁N₃O₆: 610.3393 (MH⁺). The free base wasdissolved in 4M hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 13 Preparation of(6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one,hydrochloride salt (13)

(6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one,hydrochloride salt (13) was prepared according to the following steps.

Step 1: Preparation of(6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one

(2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(synthesized as per Example 15, Step 3) (160 mg, 0.56 mmol) andpotassium thiocyanate (280 mg, 2.88 mmol) were sonicated in 5 mL ofacetic acid for 2 minutes. 8.9M Bromine in acetic acid (0.07 mL, 0.62mmol) was then added into the solution. The mixture was stirred for 3hours at 60° C. and then was concentrated. The residue was dissolved indichloromethane (10 mL) and filtered, washed with 5N aqueous sodiumhydroxide (2×30 mL), water (30 mL) and was dried over sodium sulfate.Evaporation of the solvent and purification of the residue byrecrystallization in dichloromethane yielded(6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one(180 mg, 94% yield).

Step 2: Preparation of tert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)carbamate

(6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one(180 mg, 0.15 mmol), triethyl amine (0.184 mL, 1.318 mmol) anddimethylamino pyridine (12 mg, 0.1 mmol) were dissolved in 2 mL oftetrahydrofuran. The reaction mixture was stirred at room temperaturefor 10 min and then to it was added di-tert-butyl dicarbonate (150 mg,0.68 mmol). The mixture was stirred for 4 hours at 60° C. andconcentrated. The residue was purified by flash chromatography to yieldtert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)carbamate(80 mg, 34% yield).

Step 3: Preparation of tert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate

tert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)carbamate(80 mg, 0.18 mmol), triphenyl phosphine (57 mg, 0.21 mmol), and mPEG₅-OH(45 mg, 0.18 mmol) were dissolved in 2 mL of dichloromethane. Themixture was stirred for 5 minutes at room temperature and then cooled to0° C. Diisopropyl azodicarboxylate (DIAD) (0.46 mL, 0.23 mmol) was addedinto the solution. The reaction mixture was stirred for 18 hours andthen was concentrated. The residue was purified by flash chromatographyto yield tert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate(70 mg, 57% yield).

Step 4: Preparation of(6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one,hydrochloride salt (13)

tert-butyl((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate(110 mg, 0.16 mmol) was dissolved in 1 mL of 4N hydrochloride in2-propanol and stirred at room temperature for 1 hour, and concentrated.The residue partitioned between saturated sodium bicarbonate anddichloromethane, and the organic layer dried on sodium sulfate.Evaporation of solvent yielded(6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one(13) (80 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.21 (s, 1H), 7.42(s, 1H), 6.71 (bs, 1H), 3.75-3.62 (m, 19H), 3.56-3.54 (m, 2H), 3.36 (s,3H), 3.27 (d, 1H), 2.92-2.89 (m, 1H), 2.73 (dd, 1H), 2.17-2.14 (m, 1H),2.03-1.96 (m, 2H), 1.51-1.53 (m, 1H), 1.47 (s, 3H), 0.88 (d, 3H),0.89-0.86 (m, 2H), 0.49-0.46 (m, 2H), 0.26-0.24 (m, 1H), 0.06-0.04 (m,1H). MS (ESI) for C₃₀H₄₅N₃O₆S: 576 (MH⁺). The free base was dissolved in1 mL of 4M hydrochloride in 2-propanol. The mixture was concentrated toafford product as hydrochloride salt.

Example 14 Preparation of(2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(14)

(2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(14) was prepared according to the following steps.

Step 1:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

was prepared in a manner similar to Example 7, Step 4.

Step 2: Preparation of(2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(14)

(2S,6R,11R)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate hydrochloride (120 mg, 0.33 mmol), Cs₂CO₃(214.9 mg, 0.6494 mmol) and mPEG₂-Br (78.45 mg, 0.4286 mmol) weredissolved in acetonitrile. The mixture was heated to 75° C. for 16 h andcooled to room temperature. The mixture was concentrated under vacuumand purified by flash chromatography to yield(2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(14) (51.5 mg, 47% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, 1H), 6.85(m, 2H), 4.21-4.23 (m, 2H), 3.89 (t, 2H), 3.57-3.59 (m, 2H), 3.39 (s,3H), 3.27 (d, 1H), 2.72-2.75 (m, 1H), 2.55-2.61 (m, 1H), 2.08-2.13 (m,1H), 1.87-1.94 (m, 1H), 1.45-1.48 (m, 1H), 1.41 (s, 3H), 0.85 (d, 3H);MS (ESI) for C₁₉H₂₇NO₄: 334.1965 (MH⁺). The free base was dissolved in4M hydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 15 Preparation ofN-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide(15)

N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide(15) was prepared according to the following steps.

Step 1:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

was prepared in a manner similar to Example 7, step 4.

Step 2: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(450 mg, 1.08 mmol) and benzophenone imine (292.7 mg, 1.61 mmol) weredissolved in 2 mL of toluene. BINAP (134.25 mg, 0.21 mmol), Pd₂dba₃(177.7 mg, 0.19 mmol) & Cs₂CO₃ (1053.7 mg, 3.23 mmol) were added to theabove reaction mixture and heated to 110° C. for 8-10 h. Reactionmixture was concentrated, the crude thus obtained was purified by columnchromatography; yielding(2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(400 mg, 83% yield).

Step 3: Preparation of(2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(400 mg, 0.89 mmol), hydroxylamine hydrochloride (124 mg, 1.78 mmol) andsodium ethoxide (220 mg, 2.67 mmol) were dissolved in 10 mL of MeOH. Thereaction mixture was stirred for 20 h and concentrated. The residue waspartitioned between 5 M HCl (10 mL) & ethyl acetate (10 mL). The Aq.layer was washed with MTBE and retained. The pH of aqueous layer wasadjusted to 11 and the product was extracted into dichloromethane. DCMlayer was dried over anhydrous Sodium sulfate. and concentrated undervacuum to get(2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,as a light yellow syrup (221 mg, 87% yield).

Step 4: Preparation of 2-(2-methoxyethoxy)acetic Acid

2-Methoxyethanol (10 g, 131.4 mmol) and potassium tert-butoxide (17.67g, 157.68 mmol) were dissolved in 100 mL of THF. The mixture was heatedto 45° C. for 1 h and cooled to room temperature. tert-Butylbromoacetate (25.63 g, 131.41 mmol) was added to the above mixture andstirred for 16 h at room temperature. Reaction mixture was concentrated,the residue dissolved in water. pH of the aq. layer was adjusted to12-12.5 (using 1M aq. NaOH) and stirred for 12-14 h at room temperature.Thereafter, pH of the aq. layer was adjusted to 2 using 10% aq.phosphoric acid. Product was extracted into DCM. Recovery of DCM on arotovap yielded 2-(2-methoxyethoxy)acetic acid, as an oily mass (4.1 g,23% yield).

Step 5: Preparation ofN-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide(15)

(2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(150 mg, 0.527 mmol), 2-(2-methoxyethoxy)acetic acid (5) (106 mg, 0.79mmol) and HOBT (93 mg, 0.68 mmol) were dissolved in 8 mL ofdichloromethane. DCC (131 mg, 0.633 mmol) was added and the mixture wasstirred for 70 h. RM was filtered through Celite and the bed, washedwith DCM. The filtrate was concentrated and purified using preparativeHPLC to getN-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide(15) as a yellow gum (84 mg, 40% yield). ¹H NMR (500 MHz, CDCl₃): δ9.957 (s, 1H), 7.8 (d, 1H), 7.68-7.70 (m, 2H), 4.1 (s, 2H), 3.66-3.68(m, 2H), 3.52-3.54 (m, 2H), 3.3 (s, 3H), 3.15 (d, 1H), 2.78-2.81 (m,1H), 2.45-2.48 (m, 1H), 2.05-2.06 (m, 1H), 1.82-1.96 (m, 2H), 1.41-1.44(m, 1H), 1.37 (s, 3H), 0.9 (m, 1H), 0.77-0.83 (m, 3H), 0.39-0.46 (m,2H), 0.18-0.21 (m, 1H), 0.01-0.02 (m, 2H); MS (ESI) for C₂₃H₃₂N₂O₄:400.2005 (MH⁺). The free base was dissolved in 4M hydrochloride in2-propanol. The mixture was concentrated to afford product ashydrochloride salt.

Example 16 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(16)

(2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(16) was prepared according to the following steps.

Step 1:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

was prepared in a manner similar to Example 7, step 4.

Step 2: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(800 mg, 1.92 mmol), Zn(CN)₂ (1351 mg, 5.75 mmol) and Pd(PPh₃)₄ (886 mg,0.77 mmol) were dissolved in 10 mL of DMF in sealed tube. The mixturewas heated to 130° C. for 5 h and cooled to room temperature. DMF wasconcentrated under vacuum and residue was dissolved in water. Aq. layerwas extracted with EtOAc, The organic layer was dried over sodiumsulfate and concentrated under vacuum. The residue was purified bycolumn chromatography; to afford(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile(520 mg, 92% yield).

Step 3:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylicAcid

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile (120 mg, 0.410 mmol) was dissolved inMeOH. 25% aq. KOH (5 mL) and 30% H₂O₂ (1 mL) were added to it. Reactionmix was stir heated at 85° C. for 15 h. Reaction mixture was cooled toroom temperature and diluted with water (5 mL). pH of the above mixturewas adjusted to 2-3 using 1 M aq. HCl. Compound was extracted intoEtOAc, dried over anhydrous sodium sulfate and the ethyl acetate layerwas concentrated under vacuum to afford(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylicacid (120 mg, 94% yield)

Step 4:(2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylicacid (120 g, 0.383 mmol), mPEG₁-NH₂ (31.6 mg, 0.421 mmol) and TEA (0.067mL, 0.479 mmol) was dissolved in 1.2 mL of DCM. HOBt (62 mg, 0.46 mmol)and DCC (79 mg, 0.383 mmol) were added to the above mixture and stirredfor 4 h at room temperature. Reaction mixture was filtered throughcelite and concentrated under vacuum to a residue. Residue was purifiedby column chromatography to yield(2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(16) (130 mg, 92% yield). ¹H NMR (500 MHz, DMSO-D6): δ 8.72 (t, 1H),7.85-7.90 (m, 2H), 7.79-7.81 (m, 1H), 3.42-3.48 (m, 4H), 3.27 (s, 3H),3.23 (m, 1H), 2.80-2.83 (m, 1H), 2.10-2.12 (m, 1H), 1.94-1.98 (m, 2H),1.60-1.78 (m, 3H), 1.24 (s, 3H), 0.84-0.88 (m, 1H), 0.77 (d, 3H),0.40-0.47 (m, 2H), 0.19-0.21 (m, 1H), 0.01-0.03 (m, 1H); MS (ESI) forC₂₂H₃₀N₂O₃: 371.1961 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 17 Preparation ofN,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide(17)

N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide(17) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile (320 mg, 1.09 mmol), prepared in a mannersimilar to Example 16, step 2, was dissolved in methanol. 10% Pd/C (˜50%wet) (50 mg) was added to the above mixture and reaction was underhydrogen balloon pressure for 4 h. Reaction mixture was filter throughcelite bed, the bed washed with methanol. Organic layer was concentratedunder vacuum to yield(2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(320 mg, 99% yield).

Step 2: Preparation ofN,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide

(2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(110 mg, 0.37 mmol), 2-(2-methoxyethoxy)acetic acid (64.3 mg, 0.48 mmol)and TEA (0.8 mL, 0.461 mmol) were dissolved in 1 mL of DCM. The mixturewas stirred for 10 min. Following which, HOBT (59.7 mg, 0.442 mmol) andDCC (114 mg, 0.553 mmol) were added and stirring was continued foranother 2 h. Reaction mixture was filtered and concentrated under vacuumto get a residue. The residue was purified by column chromatography toaffordN,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide(17) (62 mg, 41% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.1 (m, 1H), 7.5 (m,1H), 7.21-7.23 (m, 2H), 3.88 (s, 2H), 3.6-3.7 (m, 4H), 3.55 (s, 2H),3.37 (s, 3H), 2.85 (m, 1H), 2.92-2.95 (m, 1H), 2.63-2.67 (m, 1H),1.93-2.22 (m, 4H), 1.45 (s, 3H), 1.25 (m, 1H), 0.87-0.88 (m, 4H),0.46-0.53 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) forC₂₄H₃₄N₂O₄: 415.2243 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 18 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(18) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(18)

(2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(160 mg, 0.54 mmol) prepared in a manner similar to Example 17, step 1,and mPEG₁-Br (981 mg, 5.4 mmol) was dissolved in 1.6 mL of DMF. NaOH(214 mg, 5.4 mmol) was added to the above mixture and reaction wasstirred for 20 h at room temperature. Reaction mixture was filtered andconcentrated under vacuum to get a residue. Residue was purified bycolumn chromatography to yield(2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(18) as gummy oil (110 mg, 51% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.95(d, 1H), 7.3 (m, 2H), 3.88 (s, 2H), 3.6-3.7 (m, 4H), 3.52-3.55 (m, 2H),3.37 (s, 3H), 3.3 (m, 1H), 2.92 (m, 1H), 2.85 (m, 1H), 2.91-2.94 (m,1H), 2.72-2.76 (m, 1H), 1.97-2.13 (m, 4H), 1.34 (s, 3H), 1.25 (m, 1H),0.88-0.90 (m, 4H), 0.46-0.48 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H),MS (ESI) for C₂₄H₃₆N₂O₃: 401.2616 (MH⁺). The free base was dissolved in4M hydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 19 Preparation of(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride salt (19)

(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride salt (19) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (ketazocine)(400 mg, 1.4 mmol) and 8.9M bromine in acetic acid (0.34 mL, 3.0 mmol)were dissolved in 4 mL of acetic acid. The mixture was stirred for 18hours at 80° C. and then was concentrated. The residue was dissolved inmethanol (10 mL) and charged with 10% palladium-carbon (10% w/w). Themixture was stirred under hydrogen atmosphere for 30 minutes at roomtemperature. The reaction mixture filtered, evaporation of the solventand purification of the residue by flash chromatography yielded(2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(220 mg, 43% yield).

Step 2: Preparation of(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride salt (19)

mPEG₅-OH (770 mg, 3.0 mmol) was dissolved in 2 mL oftoluene:N,N-dimethylformamide (9:1), and sodium hydride (138 mg of 60%in mineral oil, 3.4 mmol) was added into the solution.(2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(140 mg, 0.38 mmol) and cuprous iodide (50 mg, 0.26 mmol) were thenadded under stirring. The reaction mixture was stirred at 120° C. for 3hours. 15 mL of dichloromethane was added into the reaction mixture. Thesolution was washed with water (10 mL×3) and was dried over sodiumsulfate. Evaporation of the solvent and purification of the residue byflash chromatography yielded(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(19) (90 mg, 43% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.8 (bs, 1H), 7.81(d, 1H), 6.88 (d, 1H), 4.10-4.07 (m, 1H), 3.95-3.82 (m, 5H), 3.76-3.74(m, 2H), 3.68-3.62 (m, 10H), 3.54-3.52 (m, 2H), 3.37 (s, 3H), 3.24 (bs,1H), 2.97-2.96 (m, 1H), 2.72 (dd, 1H), 2.05-1.98 (m, 1H), 1.82-1.73 (m,2H), 1.63 (s, 3H), 0.91 (d, 3H), 0.89-0.86 (m, 2H), 0.49-0.45 (m, 2H),0.25-0.24 (m, 1H), 0.07-0.04 (m, 1H). MS (ESI) for C₂₉H₄₅NO₃: 536 (MH⁺).The free base was dissolved in 4M hydrochloride in 2-propanol.Evaporation of volatiles afforded product as hydrochloride salt.

Example 20 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(20)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(20) was prepared according to the following steps.

Step 1: Preparation of S-methylO-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate

1-Phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (T. Shiyama et al., Bioorg.Med. Chem. (2004), #12, 2831) (13.0 g, 39.6 mmol) was dissolved in 250mL of tetrahydrofuran and sodium hydride (1.9 g of 60% in mineral oil,47.5 mmol) was added into the solution. The mixture was stirred for 10minutes at room temperature and then cooled to 0° C. Carbon disulfide(3.1 mL, 51.5 mmol) was then added under stirring. The reaction mixturestirred for 1 hour and then methyl iodide (3.2 mL, 51.5 mmol) was addeddrop wise at 0° C., stirred for 18 h at room temperature, andconcentrated. The residue was dissolved in ethyl acetate (200 mL) andwas washed with water (2×300 mL), brine (300 mL) and was dried oversodium sulfate. Evaporation of the solvent and purification of theresidue by flash chromatography yielded S-methylO-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate (150g, 91% yield).

Step 2: Preparation of1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol

To the suspension of 1,3-dibromo-5,5-dimethylhydantoin (34.0 g, 120.0mmol) in dichloromethane (300 mL) was added HF-pyridine (40.0 mL, 1600mmol) at −78° C., and then S-methylO-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate (15.0g, 40.0 mmol) added at same temperature. The reaction mixture wasstirred at −78° C. further for 1 hour and subsequently warmed to 0° C.and stirred at the same temperature for 2 hours. 150 mL ofdichloromethane was added into the reaction mixture. The solution waswashed with water (100 mL×3), saturated sodium bisulfite and dried oversodium sulfate. Then the crude was dissolved in MeOH and hydrogenated atroom temperature with addition of Pd—C (10%) (1.5 g) under hydrogenatmosphere. The reaction mixture was filtered and evaporated, giving the1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol (10.0 g, 86% yield).

Step 3: Preparation of1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate

To the mixture of 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol(8.0 g, 26.1 mmol), and TEA (4.7 mL, 34.0 mmol) in dichloromethane (150mL) was added methane sulfonyl chloride (2.2 mL g, 28.7 mmol) at 0° C.The reaction mixture was stirred at room temperature for 1 hour. 150 mLof dichloromethane was added into the reaction mixture. The solution waswashed with water (200 mL×3) and was dried over sodium sulfate.Evaporation of the solvent and purification of the residue by flashchromatography yielded1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate(9.0 g, 90% yield).

Step 4: Preparation ofN1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine

tert-butyl (4-aminophenyl)carbamate (Karra et. al., Bioorganic &Medicinal Chemistry Letters (2013), #23, 3081) (0.9 g, 2.3 mmol) wasdissolved in 3 mL of N,N-dimethylformamide and sodium hydride (0.112 gof 60% in mineral oil, 2.81 mmol) was added into the solution. Themixture was stirred for 10 minutes at room temperature and then cooledto 0° C. 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate (0.6 g, 2.6 mmol) was then added under stirring. Thereaction mixture was stirred for 18 hours at room temperature andconcentrated. The residue was dissolved in ethyl acetate (20 mL) and waswashed with water (2×30 mL), brine (30 mL) and was dried over sodiumsulfate. Residue obtained after evaporation was dissolved in 3 mL of 4Nhydrochloride in 2-propanol. Evaporation of volatiles afforded productas hydrochloride salt The residue partitioned between saturated sodiumbicarbonate and dichloromethane, and the organic layer dried on sodiumsulfate. Evaporation of solvent and purification of residue by flashchromatography yieldedN1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine(0.4 g, 51% yield).

Step 5:(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(20)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (prepared in a manner similar to Example 7,Step 4) (170 mg, 0.4 mmol), Pd₂dba₃ (88 mg, 0.09 mmol), BINAP (88 mg,0.13 mmol),N1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine(160 mg, 0.44 mmol) and Cs₂CO₃ (470 mg, 1.22 mmol) were suspended in 5mL of toluene. The mixture was stirred at 110° C. for 1 hour. 20 mL ofdichloromethane was added into the reaction mixture. The solution waswashed with water (10 mL×3) and was dried over sodium sulfate.Evaporation of the solvent and purification of the residue by flashchromatography yielded(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(20) (110 mg, 40% yield). δ 7.83 (d, 1H), 7.04-7.02 (m, 2H), 6.66-6.59(m, 3H), 6.59 (d, 1H), 5.85 (bs, 1H), 4.20 (bs, 1H), 4.09 (m, 2H),3.73-3.71 (m, 4H), 3.68-3.67 (m, 12H), 3.30 (t, 2H), 3.21-3.20 (m, 1H),2.92-2.90 (m, 1H), 2.74 (dd, 1H), 2.12-1.93 (m, 3H), 1.50-1.48 (m, 1H),1.33 (s, 3H), 0.91 (d, 3H), 0.89-0.86 (m, 2H), 0.47-0.43 (m, 2H),0.26-0.24 (m, 1H), 0.07-0.04 (m, 1H). MS (ESI) for C₃₅H₄₈F₃N₃O₆: 664(MH⁺). The free base was dissolved in 4M hydrochloride in 2-propanol.The mixture was concentrated to afford product as hydrochloride salt.

Example 21 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(21)

(2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(21) was prepared according to the following steps.

Step 1: Preparation of16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine

16-(Benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-yl methanesulfonate(500 mg, 0.11 mmol) was dissolved in 5 mL of acetonitrile in a sealedtube. 25% aq. ammonia (5 mL) was added and reaction mixture was heatedat 80 C for 16 h. Reaction mixture was cooled to room temperature andcompound was extracted into EtOAc, dried over anhydrous sodium sulfate,conc. under vacuum to get crude compound. Crude was purified by columnchromatography, to afford16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine (300 mg, 72.8%yield) as a thick yellow colored liquid.

Step 2: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate(300 mg, 0.719 mmol) prepared in a manner similar to Example 7, step 4and 16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine (293 mg,0.719 mmol) were dissolved in toluene. BINAP (89.6 mg, 0.144 mmol),Pd₂(dba)₃ (118 mg, 0.0129 mmol) & Cs₂CO₃ (705 mg, 0.215 mmol) were addedto the above mixture and heated to 110° C. for 2 h. The mixture wascooled to room temperature and conc. under vacuum. Crude was purified bycolumn chromatography to yield(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(200 mg, 43.6% yield).

Step 3: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(200 mg). 10% Pd/C (˜50% wet) (40 mg) was added to the above mixture andreaction was stirred under hydrogen gas (balloon pressure) for 4 h.Reaction mixture was filtered through celite bed and the bed was washedwith methanol. Organic layer was conc. under vacuum to yield(2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(21) (125 mg, 81.7% yield). ¹H NMR (500 MHz, CDCl₃): δ7.9 (m, 1H), 7.6(m, 1H), 7.4 (s, 1H), 4.05 (m, 1H), 3.9 (m, 2H), 3.6-3.7 (m, 16H), 3.55(s, 2H), 3.37 (s, 3H), 2.85 (m, 1H), 2.92-2.95 (m, 1H), 2.63-2.67 (m,1H), 1.93-2.22 (m, 4H), 1.45 (s, 3H), 1.25 (m, 1H), 0.87-0.88 (m, 4H),0.46-0.53 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) forC₃₀H₄₆N₂O₇: 549.3317 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 22 Preparation of(7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one(22)

(7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one(22) was prepared according to the following steps.

Step 1: Preparation of1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea

(2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(prepared in a manner similar to Example 15, Step 3) (60 mg, 0.21 mmol),and O,O-di(pyridin-2-yl) carbonothioate (49 mg, 0.22 mmol) weredissolved in 2 mL of tetrahydrofuran. The mixture was stirred for 2hours at 65° C. and then cooled to room temperature. mPEG₅-NH₂ (53 g,0.22 mmol) was added into the solution. The reaction mixture was stirredfor 1 hour and then was concentrated. Residue was purified by flashchromatography to yield1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea(70 mg, 57% yield)

Step 2: Preparation of(7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one(22)

1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea(120 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane andbenzyltrimethyl ammonium tribromide (80 mg, 0.2 mmol) was added into thesolution. The reaction mixture was stirred at room temperature for 18hours. 20 mL of dichloromethane was added into the reaction mixture. Thesolution was washed with 5% aqueous NaHCO₃ (30 mL), water (10 mL×3) andwas dried over sodium sulfate. Evaporation of the solvent andpurification of the residue by flash chromatography yielded(7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one(22) (55 mg, 46% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, 1H), 7.43(d, 1H), 6.43 (bs, 1H), 3.75-3.63 (m, 19H), 3.55-3.53 (m, 2H), 3.36 (s,3H), 3.27 (d, 1H), 2.92-2.89 (m, 1H), 2.71 (dd, 1H), 2.16-2.13 (m, 1H),2.01-1.82 (m, 2H), 1.63 (s, 3H), 0.96 (d, 3H), 0.89-0.86 (m, 2H),0.48-0.45 (m, 2H), 0.26-0.23 (m, 1H), 0.06-0.02 (m, 1H). MS (ESI) forC₃₀H₄₅N₃O₆S: 576 (MH⁺). The free base was dissolved in 1 mL of 4Mhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 23 Preparation of(2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(23)

(2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(23) was prepared according to the following steps

Step 1: Preparation of tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate

2-Amino-2-methyl-1-propanol (5 g, 56.1 mmol), (Boc)₂O (13.46 g, 61.7mmol) and triethyl amine (6.24 g, 61.7 mmol) were dissolved in 50 mL ofdichloromethane. The reaction mixture was stirred for 4 h at 22 to 25°C. Above mixture was washed with water (25 mL×2), dried over anhydroussodium sulfate and concentrated under vacuum to get tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (10.3 g, 97% yield).

Step 2: Preparation of tert-butyl(1-(benzyloxy)-2-methylpropan-2-yl)carbamate

tert-Butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (2) (2 g, 10.57mmol), potassium hydroxide (1.10 g, 19.55 mmol), and benzyl bromide(3.34 g, 19.55 mmol) were dissolved in 20 mL of DMF. The mixture wasstirred for 2 h and concentrated under vacuum. Crude was purified bycolumn chromatography yielded tert-butyl(1-(benzyloxy)-2-methylpropan-2-yl)carbamate (2.65 g, 90% yield).

Step 3: Preparation of 1-(benzyloxy)-2-methylpropan-2-amine

tert-Butyl (1-(benzyloxy)-2-methylpropan-2-yl)carbamate (2 g, 7.16 mmol)was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1 hand concentrated under vacuum. The residue was dissolved in 50 mL ofwater and pH was adjusted to 9.0 using 1M aq. NaOH. The compound wasextracted into ethyl acetate, dried over anhydrous sodium sulfate,concentrated under vacuum to yield 1-(benzyloxy)-2-methylpropan-2-amineas brown gum (0.90 g, 70% yield).

Step 4: Preparation of(2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (0.450 mg, 1.078 mmol) and1-(benzyloxy)-2-methylpropan-2-amine (0.193 g, 1.078 mmol) weredissolved in toluene. BINAP (0.199 g, 0.32 mmol), Pd₂dba₃ (0.198 g,0.216 mmol) and Cs₂CO₃ (0.490 g, 1.51 mmol) were added to the abovemixture and heated to 110° C. for 3 h. The mixture was cooled to roomtemperature and concentrated under vacuum. Crude was purified by flashchromatography to yield(2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(200 mg, 42% yield).

Step 5: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(23)

(2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(190 mg, 0.425 mmol) was dissolved in 10 mL of methanol. 10% Pd/C (˜50%wet) (20 mg) was added to the above mixture and the reaction wasperformed under hydrogen balloon pressure for 4 h. Reaction mixture wasfiltered through a celite bed and washed with methanol. Evaporation ofsolvent under vacuum yielded(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(160 mg, 99% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 11.36 (bs, 1H), 7.71(d, 1H), 6.69-6.73 (m, 3H), 3.86 (bs, 1H), 3.4-3.43 (m, 2H), 3.17 (s,1H), 3.06-3.16 (m, 1H), 2.6-2.67 (m, 3H), 2.24-2.31 (m, 1H), 1.63-1.66(m, 1H), 1.37 (m, 3H), 1.23-1.29 (m, 10H), 0.81-0.87 (m, 3H), 0.6-0.63(m, 2H), 0.47-0.49 (m, 2H); MS (ESI) for C₂₂H₃₂N₂O₂: 357.2401 (MH⁺). Thefree base was dissolved in 4M hydrochloride in 2-propanol. The mixturewas concentrated to afford product as hydrochloride salt.

Example 24 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(24)

(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(24) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (1,3-dihydroxypropan-2-yl)carbamate

Serinol (2.00 g, 21.96 mmol) and (Boc)₂O (4.80 g, 21.96 mmol) wasdissolved in 20 mL of dichloromethane. The reaction mixture was stirredfor 4 h at 22 to 25° C. The above mixture was washed with water (25mL×2), dried over anhydrous sodium sulfate and concentrated under vacuumto yield tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (4.1 g, 97%yield).

Step 2: Preparation of tert-butyl(1,3-bis(benzyloxy)propan-2-yl)carbamate

tert-Butyl (1,3-dihydroxypropan-2-yl)carbamate (3.7 g, 19.35 mmol),potassium hydroxide (4.0 g, 71.59 mmol), and benzyl bromide (12.24 g,71.59 mmol) were dissolved in 50 mL of DMF. The mixture was stirred for2 h and concentrated under vacuum. The crude product was purified usingcolumn chromatography to yield tert-butyl(1,3-bis(benzyloxy)propan-2-yl)carbamate (3.25 g, 45% yield).

Step 3: Preparation of 1,3-bis(benzyloxy)propan-2-amine

tert-butyl (1,3-bis(benzyloxy)propan-2-yl)carbamate (3.00 g, 8.076 mmol)was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1hour and concentrated under vacuum. The residue was dissolved in 50 mLof water and pH was adjusted to 9.0 using 1M aq. NaOH. The compound wasextracted into ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under vacuum to yield 1,3-bis(benzyloxy)propan-2-amine as abrown gum (2.00 g, 91% yield).

Step 4: Preparation of(2S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (0.450 mg, 1.078 mmol) and1,3-bis(benzyloxy)propan-2-amine (0.351 g, 1.29 mmol) were dissolved intoluene. BINAP (0.199 g, 0.32 mmol), Pd₂dba₃ (0.198 g, 0.216 mmol) andCs₂CO₃ (0.490 g, 1.51 mmol) were added to the above mixture and heatedto 110° C. for 3 hours. The mixture was cooled to room temperature andconcentrated under vacuum. Crude on purification using flashchromatography yielded(2S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.545 g, 94% yield).

Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(24)

(2S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.545 g, 1.01 mmol) was dissolved in 10 mL of methanol. 10% Pd/C (˜50%wet) (50 mg) was added to the above mixture and reaction was performedunder hydrogen balloon pressure for 4 hours. The reaction mixture wasfilter through a celite bed and washed with methanol. Concentration ofthe organic layer under vacuum yielded(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.350 g, 97% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 10.99 (bs, 1H), 7.72(d, 1H), 6.9-6.96 (m, 1H), 6.59-6.67 (m, 2H), 3.87 (bs, 1H), 3.41-3.52(m, 10H), 3.17 (s, 1H), 3.08-3.12 (m, 1H), 2.57-2.68 (m, 3H), 2.19-2.25(m, 1H), 1.65-1.67 (m, 1H), 1.38 (m, 3H), 1.22-1.29 (m, 3H), 0.81-0.86(m, 3H), 0.6-0.62 (m, 2H), 0.47-0.48 (m, 2H); MS (ESI) for C₂₂H₃₂N₂O₂:359.2196 (MH⁺). The free base was dissolved in 4M hydrochloride in2-propanol. The mixture was concentrated to afford product ashydrochloride salt.

Example 25 Preparation of(1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol(25)

(1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol(25) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(1.0 g, 3.5 mmol) was dissolved in 20 mL of acetonitrile and cesiumcarbonate (4.5 g, 14.0 mmol) was added into the solution. The mixturewas stirred for 10 minutes at 60° C. Benzyl bromide (0.4 mL, 3.5 mmol)was then added under stirring. The reaction mixture stirred for 1 hourat 60° C., filtered and concentrated. The residue was dissolved in ethylacetate (60 mL) and was washed with water (2×50 mL), dried overanhydrous sodium sulfate. Evaporation of the solvent and purification ofresidue by flash chromatography yielded(2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(1.2 g, 91% yield).

Step 2: Preparation of(1R,2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol

To the solution of(2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(1.0 g, 2.6 mmol) in tetrahydrofuran (30 mL) was added 1M lithiumaluminium hydride solution in THF (2.6 mL, 2.6 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 18 hours. 10 mL ofethyl acetate was added into the reaction mixture. The suspension waspassed through plug of celite. Evaporation of the solvent andpurification of the residue by flash chromatography yielded(1R,2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol(0.7 g, 69% yield).

Step 3: Preparation of(1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine

(1R,2S,6R,11R)-8-(Benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol(0.7 g, 1.8 mmol) was dissolved in 3 mL of N,N-dimethylformamide andsodium hydride (0.148 g of 60% in mineral oil, 3.7 mmol) was added intothe solution. The mixture was stirred for 10 minutes at room temperatureand then heated to 70° C. mPEG₅-OMs (0.86 g, 2.6 mmol) was then addedunder stirring. The reaction mixture was stirred 70° C. for 18 h.Reaction mixture was dissolved in ethyl acetate (20 mL) and was washedwith water (2×50 mL), brine (30 mL) and was dried over any sodiumsulfate. Evaporation of solvent and purification of residue by flashchromatography yielded of(1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine(0.4 g, 35% yield).

Step 4: Preparation of(1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol(25)

(1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine(0.400 g, 0.4 mmol) was dissolved in MeOH and hydrogenated at roomtemperature with addition of Pd—C (10%) (0.100 g) under hydrogenatmosphere. The reaction mixture filtered and evaporated and thepurification of residue by flash chromatography yielded(1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol(0.170 g, 49% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.47 (d, 1H), 6.74 (dd,1H), 6.64 (d, 1H), 5.85 (bs, 1H), 4.54 (d, 1H), 3.94-3.95 (m, 1H),3.57-3.74 (m, 19H), 3.39 (s, 3H), 3.17 (t, 1H), 2.96 (dd, 1H), 2.81 (dd,1H), 2.63 (dd, 1H), 2.48 (dt, 1H), 2.04-2.10 (m, 1H), 1.78 (dt, 1H),1.30 (s, 3H), 1.13-1.15 (m, 1H), 0.87 (d, 3H), 0.79-0.81 (m, 1H),0.47-0.52 (m, 1H), 0.36-0.42 (m, 1H), 0.06-0.12 (m, 2H). MS (ESI) forC₂₉H₄₇NO₇: 522 (MH⁺). The free base (170 mg) was dissolved in 2 mL of 4Nhydrochloride in 2-propanol. The mixture was concentrated to affordproduct as hydrochloride salt.

Example 26 Preparation of(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride Salt (26)

(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride salt (26) was prepared according to the following steps.

Step 1: Preparation of(2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.450 g, 1.2 mmol) was dissolved in 10 mL of acetonitrile and cesiumcarbonate (0.80 g, 2.4 mmol) was added into the solution. The mixturewas stirred for 10 minutes at 60° C. Benzyl bromide (0.15 mL, 1.2 mmol)was then added under stirring. The reaction mixture stirred for 1 hourat 60° C., filtered and concentrated. The residue was dissolved in ethylacetate (20 mL) and was washed with water (2×20 mL), dried over sodiumsulfate. Evaporation of the solvent and purification of the residue byflash chromatography yielded(2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.450 g, 80% yield).

Step 2: Preparation of(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.370 g, 0.8 mmol), BrettPHOS palladacycle (0.065 g, 0.08 mmol),BrettPHOS (0.044 g, 0.08 mmol), 2,5,8,11,14-pentaoxahexadecan-16-amine(0.37 g, 1.4 mmol) and 2M Sodium ter-butoxide solution in THF (1.2 mL,2.4 mmol) were suspended in 3 mL of toluene. The mixture was stirred at90° C. for 4 hours. 20 mL of ethyl acetate was added into the reactionmixture. The solution was washed with water (2×10 mL) and was dried oversodium sulfate. Evaporation of the solvent and purification of theresidue by flash chromatography yielded(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.200 g, 40% yield).

Step 3: Preparation of(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,hydrochloride salt (26)

(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.220 g, 0.35 mmol) was dissolved in MeOH and hydrogenated at roomtemperature with addition of Pd—C (10%) (˜50% wet) (0.050 g) underhydrogen atmosphere. The reaction mixture filtered and evaporated, andthe purification of residue by flash chromatography yielded(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.105 g, 55% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.3-8.7 (bs, 1H), 7.87(d, 1H), 6.89 (d, 1H), 3.72-3.78 (m, 4H), 3.62-3.69 (m, 14H), 3.53-3.57(m, 2H), 3.37 (s, 3H), 3.21 (d, 1H), 3.08-3.12 (m, 2H), 2.97-2.98 (m,1H), 2.91-2.94 (m, 1H), 2.71 (dd, 1H), 1.92-2.03 (m, 2H), 1.73-1.75 (m,1H), 1.65 (s, 3H), 0.93 (d, 3H), 0.83-0.90 (m, 1H), 0.43-0.49 (m, 2H),0.22-0.24 (m, 1H), 0.03-0.06 (m, 1H). MS (ESI) for C₂₉H₄₆N₂O₇: 535(MH⁺). The free base (100 mg) was dissolved in 2 mL of 4N hydrochloridein 2-propanol. The mixture was concentrated to afford product ashydrochloride salt.

Example 27 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(27)

(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(27) was prepared according to the following steps.

Step 1: Preparation of 1-(2-methoxyethyl)piperidin-4-amine

4-amino piperidine (2 g. 19.96 mmol) and anhydrous sodium carbonate(5.29 g, 49.9 mmol) was dissolved in 25 mL of methyl isobutyl ketone.The heterogeneous reaction mass was heated to reflux, and maintained for4 h. 2-Methoxyethyl methanesulfonate (2.77 g, 17.96 mmol) was added tothe above mixture and stirred for 16 h at 22 to 25° C. The reaction masswas filtered and 25 mL of 1N aq.HCl was added and stirred for another 1h. The aqueous phase was separated, and pH was adjusted to 11.0 using INaq. NaOH. Compound was extracted into DCM, dried over anhydrous sodiumsulfate and conc under vacuum to get 1-(2-methoxyethyl)piperidin-4-amine((300 mg, 9.5% yield)

Step 2: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(27)

(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (0.350 g, 0.8384 mmol) and1-(2-methoxyethyl)piperidin-4-amine (0.159 g, 1.006 mmol) were dissolvedin toluene. BINAP (0.156 g, 0.2515 mmol), Pd₂dba₃ (0.153 g, 0.1676 mmol)& Cs₂CO₃ (0.39 g, 1.1737 mmol) were added to the above mixture andheated to 110° C. for 2 h. The mixture was cooled to room temperatureand concentrated under vacuum. Crude was purified by silica gel columnchromatography to get pure(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(0.170 g, 48% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.8 (d, 1H), 7.68-7.70(m, 2H), 3.5 (t, 2H), 3.35 (s, 3H), 3.15 (d, 1H), 2.9 (m, 2H), 2.78-2.81(m, 1H), 2.65 (m, 2H), 2.55 (t, 2H), 2.45-2.48 (m, 1H), 2.05-2.06 (m,2H), 1.82-1.96 (m, 3H), 1.41-1.44 (m, 3H), 1.37 (s, 3H), 1.1-1.3 (m,2H), 0.9 (m, 1H), 0.77-0.83 (m, 3H), 0.39-0.46 (m, 2H), 0.18-0.21 (m,1H), 0.01-0.02 (m, 2H); MS (ESI) for C₂₆H₃₉N₃O₂: 426.3116 (MH⁺). Thefree base was dissolved in 2 mL of 4N hydrochloride in 2-propanol. Themixture was concentrated to afford product as hydrochloride salt.

Example 28 Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(1)

(2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(28) was prepared according to the following steps

Step 1: Preparation of tert-butyl4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate

To a mixture of tert-butyl piperazine-1-carboxylate (2 g, 10.74 mmol),K₂CO₃ (4.45 g, 32.22 mmol) in acetone (20 mL) was charged2-(2-(2-methoxyethoxy)ethoxy)ethyl methanesulfonate (2.86 g, 11.81mmol). The mixture was stirred for four hours at 50° C. The reactionmass was concentrated under vacuum. The obtained crude was dissolved inEtOAc (20 mL) and washed with water (10 mL×2) and brine (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum to give tert-butyl4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate (2.49 g,70% yield) as a brown color gum.

Step 2: Preparation of 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine

To a mixture of tert-butyl4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate (1.0 g,3.00 mmol) in DCM (10 mL), was added 4.0 M HCl in IPA (1 mL) at ambienttemperature. The mixture was stirred for two hours, and washed withsaturated NaHCO₃ (15 mL×2), water (10 mL×1) and brine (10 mL×1). Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated undervacuum to give 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine (0.63 g,90% yield) as a brown gum.

Step 3: Preparation of(2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(28)

(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (200 mg, 0.479 mmol) and1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine (122 mg, 0.527 mmol)were dissolved in toluene. BINAP (98 mg, 0.144 mmol), Pd₂dba₃ (88 mg,0.096 mmol) and Cs₂CO₃ (219 mg, 0.671 mmol) were added to the abovemixture and heated to 110° C. for two hours. The mixture was cooled toroom temperature and concentrated under vacuum. A crude product waspurified by column chromatography to obtain a pure(2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one(28) (124 mg, 55% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.8 (d, 1H),7.70-7.65 (m, 2H), 4.05 (br, s, 1H), 3.7-3.54 (m, 10H), 3.45 (s, 3H),3.40-3.25 (m, 8H), 2.57-2.51 (m, 4H), 2.35-2.28 (m, 4H), 2.20 (t, 2H),1.41-1.44 (m, 3H), 1.37 (s, 3H), 0.46-0.39 (m, 2H), 0.21-0.18 (m, 1H),0.20-0.10 (m, 2H); MS (ESI) for C₂₉H₄₅N₃O₄: 500.39 (MH⁺). The free basewas dissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

It is understood that each of Examples 1-28 described above may bemodified to introduce oligomers of various lengths for each compound, asdisclosed herein.

Example 29 Radioligand Competition Binding Assay

The binding affinities of certain compounds of the present inventionwere evaluated using radioligand binding assays in membranes preparedfrom CHO-K1 cells expressing recombinant human kappa (KOR) or mu (MOR)opioid receptors.

Competition binding experiments were conducted by incubating membraneprotein to equilibrium in triplicate in the presence of a fixedconcentration of radioligand and increasing concentrations of testcompound for evaluation of binding to KOR or single concentration (10μM) of test compound for evaluation of binding to MOR in 101 μL finalvolume. The radioligands used were specific for each receptor type, andthe assay conditions are described in Table 1. Following incubations,the membranes were rapidly filtered through GF/B filter plate (presoakedwith 0.5% polyethyleneimine), washed five times with cold 50 mMTris-HCl, pH 7.5, and the bound radioactivity was then measured byliquid scintillation counting. Non-specific binding was measured in thepresence of excess ligand; this value was subtracted from the totalbinding to yield the specific binding at each test concentration. Assayconditions are reported in Table 1 below.

TABLE 1 Non- Receptor Membrane specific Receptor Source ProteinRadioligand K_(d) binding Methods Kappa Human 2.5 [³H] 0.3 U-50488Reaction in 50 mM Tris-HCl Opioid recombinant μg/well Diprenorphine nM(10 μM) (pH 7.5), 5 mM MgCl₂, 0.05% in CHO-K1 (1 nM) BSA at roomtemperature for 1 h cells with shaking Mu Opioid Human 5 μg/well [³H]Naloxone — Naloxone Reaction in 50 mM Tris-HCl recombinant (4 nM) (10μM) (pH 7.5), 5 mM MgCl₂ at room in CHO-K1 temperature for 1 h withshaking cells

For KOR binding, IC₅₀ (concentration of test compound required toinhibit 50% of specific binding) values were obtained from non-linearregression analysis of dose-response curves, using GraphPad's Prism 5.01software, and were calculated for those compounds that showed >50%inhibition of specific binding at the highest concentration tested.K_(i) (affinity of test compound) was obtained using the Cheng Prusoffcorrection using experimental K_(d) (affinity of radioligand) valuesthat were previously determined under these assay conditions. For MORbinding, compounds were tested at one concentration, 10 μM, to evaluateits ability to inhibit specific radioligand binding. The values areexpressed as percent inhibition of specific binding and greater than 50%inhibition of binding was considered to be significant.

With respect to determining MOR binding, an approach similar to one usedfor KOR binding was used.

Data are expressed as means of one experiment in triplicatedetermination and reported in Table 2.

TABLE 2 Binding Activities of Selected Compounds Kappa Mu receptorreceptor binding % inhibition Compound at single No. concentration Mureceptor (Example IC50 % inhib binding No.) (nM) Ki (nM) @ 10 uM IC50(nM) Ki (nM) 1 2682 618.9 81.9 — — 2 2380 549.2 85.5 — — 3 3333 769.280.6 — — 4 879 202.9 89.2 — — 5 12820 2959 51.2 — — 6 6079 1403 48.6 — —12 5.004 58.48 20 2.861 44.3 23 1055 7957 24 493.9 1807 25 955.2 3918Ketazocine 5.6 1.3 99.2 8.4

Ketazocine was assayed as a known kappa and mu opioid agonist. Thenotation “--” indicates that the assay was not performed for thereferenced compounds.

Example 30 cAMP Accumulation Assay

Inhibition of cAMP accumulation by select compounds was measured inforskolin-stimulated CHO-K1 cells stably expressing KOR. CHO-K1 cellsstably expressing KOR were harvested using Invitrogen Cell DissociationBuffer, and then centrifuged at 1200 rpm for five minutes. Thesupernatant was aspirated and cells were resuspended in assay buffer toa density of 4×10⁵ cells/mL. 25 μL of cells were added into a whitehalf-area 96 well plate. Fourteen point serial dilutions of testcompounds were carried out in assay buffer (PBS with 0.5 mM IBMX).Ketazocine was used as a positive control for each assay. 12.5 μL ofcompound was added to the cells in duplicate for each testconcentration. The cells were then stimulated with 12.5 μL forskolin ata final concentration 20 μM. Cells were incubated for 45 minutes in a37° C., 5% CO₂ water jacketed incubator. CisBio HTRF cAMP assay reagentwas used for cAMP quantitation. Two hours after substrate addition,signal at 665/615 nm was measured using the Perkin Elmer Victor X4 HTRFreader. Data analysis was done using GraphPad Prism, sigmoidaldose-response (variable slope) curve fitting.

Using a similar approach, inhibition of cAMP accumulation by selectcompounds was also determined in forskolin-simulated CHO-K1 cells stablyexpressing MOR (wherein for this assay a density of 8×105 cells/mL wasused and the positive control was DAMGO). Certain compounds of thepresent invention were tested as described above. Data is reported inTable 3 below.

TABLE 3 EC50 cAMP EC50 cAMP Compound (nM) - KOR (nM) - MOR 1 153 2 139 3122 4 9.35 5 350 6 357 12 7 189.1 20 6.1 127.9 23 395.2 3288 24 106.8597.8 25 195 1209 Ketazocine 0.55

The data in Table 3 indicates that the tested compounds were effectivein reducing cAMP in cells following KOR and MOR binding, indicating thatthe compounds function as agonists at the kappa and mu opioid receptors.

Example 31 In Situ Rat Brain Perfusion

The in situ perfusion experiment measures the relative permeability ofcompounds across a model of the blood-brain barrier. In situ perfusionof opioids into rat brain is performed as described in Summerfield etal., J Pharmacol Exp Ther 322: 205-213 (2007).

Adult male Sprague Dawley rats are used for the study. Rats areanaesthetized and the left common carotid artery is surgicallycannulated for perfusion. Test compounds are perfused at concentrationsof 5-50 μM in a Krebs Ringer perfusion buffer (pH 7.4). Atenolol andantipyrine are included as low and moderate permeability markers,respectively. At the end of a 30 second perfusion, the brains areremoved, the left brain hemisphere is excised and homogenized. Testcompounds are extracted and analyzed using LC-MS/MS. The brainpermeability of the test compounds is calculated as follows:

P=Kin/S,

where P is the permeability in cm/s, Kin is the unidirectional transferconstant (ml/min/gram), and S is the luminal area of the brain vascularspace.

The relative permeability as determined in the in situ brain perfusionexperiment provides information regarding the rates at which compoundsenter the central nervous system from the periphery. It is used tocharacterize and compare the degree to which compounds of the presentinvention penetrate the BBB as compared to known compounds or analogs ofthe tested compounds.

Example 32 Acetic Acid Writhing

An analgesic assay was used to determine whether a given compound canreduce and/or prevent visceral pain in mice. The assay utilizes SwissAlbino or CD-1 male mice (5-10 mice per group), each mouse beingapproximately 0.015-0.030 kg on the study day. Mice were treatedaccording to standard protocols.

Mice were given a single “pretreatment” dose of a compound of thepresent invention, a known compound, such as diclofenac (which is aknown analgesic which has been shown to reduce writhing behavior in thismodel), or control solution at fifteen minutes (for subcutaneous route)or thirty minutes (for orally route) prior to the administration of theacetic acid solution. The animal was given an intraperitoneal (IP)injection of an irritant (acetic acid) that induces “writhing” which mayinclude: contractions of the abdomen, twisting and turning of the trunk,arching of the back and the extension of the hindlimbs. Mice are given asingle IP injection (0.1 mL/10 g bodyweight) of a 0.5% acetic acidsolution. After the injection the animals were returned to theirobservation enclosure and their behavior was observed. Contractions werecounted between 0 and 20 minutes after the injection. The animals wereused once. In certain instances, the test articles were administered atmultiple doses to determine a dose response curve.

Table 4 provides the results for certain compounds of the presentinvention that were administered subcutaneously. Table 5 provides theresults for certain compounds of the present invention that wereadministered orally.

TABLE 4 AAW Efficacy Following Subcutaneous Administration Example No.Dose (mg/kg) % Efficacy ketazocine 0.01 10.57 0.1 50.03 1 100.00 4 3 0.010 39.7 30 100.0 7 3 38.8 30 84.8 8 3 38.0 30 100.0 9 0.3 13.3 3 67.8 361.4 10 95.4 30 99.2 10 3 34.0 30 100.0 11 0.3 21.1 3 62.2 3 64.3 1099.1 30 100.0 12 3 68.6 30 100.0 15 10 100.0 16 10 26.4 13 10 40.2 Step1 of 13 10 100 17 10 23.3 14 10 13.2 18 10 31.9 19 10 31.6 20 10 88.1

TABLE 5 AAW Efficacy following Oral Administration Example No. Dose(mg/kg) % Efficacy ketazocine 0.1 12.8 1 34.5 10 58.9 100 100.0 4 2003.8 9 10 38.5 11 10 31.2 12 0.1 22.5 1 56.9 10 97.2 10 90.2 20 0.3 39.13 79.5 30 100.0

In some instances, the percent efficacy following subcutaneousadministration reported in Table 4 was derived with outlier data. If theoutlier data is removed, the following percent efficacy values areobtained: Compound 7 (3 mg/kg)—31.95; Compound 8 (3 mg/kg)—31.07;Compound 9 (0.3 mg/kg)—13.18, (3 mg/kg)—64.20, (3 mg/kg)—57.09 and (10mg/kg)—94.93; Compound 10 (3 mg/kg)—26.63; Compound 11 (0.3mg/kg)—12.30, (3 mg/kg)—56.21, (3 mg/kg)—60.30 and (10 mg/kg)—99.00; andCompound 12 (3 mg/kg)—65.09.

Example 33 Locomotor Activity

Male Swiss Albino mice were treated orally with vehicle (0.5% HPMC+0.1%Tween80), ketazocine, Compound 12 (0.3, 3 and 30 mg/kg) or Compound 20(0.3, 3 and 30 mg/kg) thirty minutes prior to placement in the locomotoractivity chamber. Total distance traveled was measured over the twentyminute observation time following placement in the locomotor activitychamber. Data are normalized relative to percent distance traveled inthe vehicle group. The efficacy of Compound 12 (reported as percentdistance traveled in comparison to vehicle) was 88.85%, 83.74% and 0.08%at 0.3, 3 and 30 mg/kg dosages, respectively, while the locomotoractivity of Compound 20 (reported as percent distance traveled incomparison to vehicle) was 100%, 88% and 0.03% at 0.3, 3 and 30 mg/kgdosages, respectively.

What is claimed is:
 1. A compound selected from the formula:

wherein: R¹ is selected from hydrogen, optionally substituted alkyl,optionally substituted aryl, and X-POLY; R² is selected from optionallysubstituted alkyl and —X-POLY; R³ is selected from hydroxyl, optionallysubstituted alkyl, optionally substituted amino, optionally substitutedheterocyclyl, and —X-POLY; or R¹ and R³ are taken together with theirintervening atoms to form a fused, optionally substituted heteroaryl oroptionally substituted heterocyclyl; or R³ and R⁵ are taken togetherwith their intervening atoms to form a fused, optionally substitutedheteroaryl;

is optionally a single bond or a double bond; G is —O—R⁴ or NH—R⁴ when

represents a single bond or G is ═O or ═N—R⁴ when

represents a double bond; X is a spacer moiety (e.g. a covalent bond,—C(O)—, —NHC(O)—, —NH—, —CH₂CHOHCH₂NH—, and —O—); POLY is a watersoluble, non-peptidic oligomer; R⁴ is -L-POLY or —X-POLY, wherein L isan optional amino acid residue; R⁵ is selected from hydrogen and X-POLY;and provided one of R¹, R², R³, R⁴, and R⁵ comprises a POLY group; andpharmaceutically acceptable salts and solvates thereof.
 2. The compoundof claim 1, wherein R⁵ is hydrogen.
 3. The compound of any one of thepreceding claims, wherein R² is alkyl.
 4. The compound of any one of thepreceding claims, wherein R² is cyclopropylmethyl.
 5. The compound ofany one of the preceding claims, wherein G is O and

represents a double bond.
 6. The compound of any one of the precedingclaims, wherein R¹ is hydrogen.
 7. The compound of any one of thepreceding claims, wherein R³ is selected from optionally substitutedalkyl, optionally substituted amino, and —X-POLY.
 8. The compound of anyone of the preceding claims, wherein R³ is optionally substituted amino.9. The compound of any one of the preceding claims, wherein R³ is aminosubstituted with an optionally substituted aryl or optionallysubstituted alkyl.
 10. The compound of any one of the preceding claims,wherein R³ is amino substituted with an optionally substituted phenyl.11. The compound of any one of the preceding claims, wherein thecompound of Formula I is selected from a compound of the formula

wherein: q is an integer from 1 to 3; each R^(a) is independentlyselected from optionally substituted amino, halo, optionally substitutedalkyl, and X-POLY; X is selected from a covalent bond, —NH— or —O—; POLYis a water soluble, non-peptidic oligomer; and wherein only one R^(a) is—X-POLY.
 12. The compound of claim 11, wherein q is
 1. 13. The compoundof any one claim 11 or 12, wherein X is —NH—.
 14. The compound of anyone of claims 11 or 12, wherein X is —O—.
 15. The compound of any one ofclaims 11 to 14, wherein POLY is a poly(alkylene oxide) oligomer. 16.The compound of any one of claims 11 to 15, wherein POLY is apoly(ethylene oxide) oligomer.
 17. The compound of any one of claims 11to 16, wherein POLY is capped with an optionally substituted alkyl. 18.The compound of any one of claims 11 to 17, wherein POLY is capped witha methyl, trifluoromethyl, or methyl substituted with a carboxy group.19. The compound of any one of claims 11 to 18, wherein the compound ofFormula II is selected from a compound of the formula

wherein: R is selected from methyl, trifluoromethyl, and methylsubstituted with a carboxy group; n is an integer from 1 to 30; and X is—O— or —NH—.
 20. The compound of claim 19, wherein X is —O—.
 21. Thecompound of claim 19, wherein X is —NH—.
 22. The compound of any one ofclaims 19 to 21, wherein n is an integer from 1 to
 10. 23. The compoundof any one of claims 19 to 21, wherein the compound of Formula III ischosen from a compound of the formula:

wherein n is an integer from 1 to
 30. 24. The compound of claim 23,wherein n is an integer from 1 to
 10. 25. The compound of any one ofclaims 1 to 7, wherein R³ is an optionally substituted alkyl.
 26. Thecompound of claim 25, wherein R³ is an optionally substituted loweralkyl.
 27. The compound of claim 25 or 26, wherein R³ is a lower alkylgroup substituted with an optionally substituted amino group or anoptionally substituted acylamino group.
 28. The compound of any one ofclaims 25 to 27, wherein the compound of formula I is selected from acompound of the formula

wherein n is an integer from 1 to
 30. 29. The compound of claim 28,wherein n is an integer from 1 to
 10. 30. The compound of any one ofclaims 25 to 27, wherein the compound of formula I is selected from acompound of the formula

wherein n is an integer from 1 to
 30. 31. The compound of claim 30,wherein n is an integer from 1 to
 10. 32. The compound of any one ofclaims 1 to 7, wherein R³ is —X-POLY.
 33. The compound of claim 32,wherein the compound of Formula I is selected from a compound of theformula

wherein X is selected from —O—, —NHC(O)—, —CH₂CHOHCH₂NH—, and —NH—; andPOLY is a poly(alkylene oxide) oligomer.
 34. The compound of any one ofclaims 32 and 33, wherein X is —O—.
 35. The compound of any one ofclaims 32 and 33, wherein X is —NH—.
 36. The compound of any one ofclaims 32 and 33, wherein X is —NHC(O)—.
 37. The compound of any one ofclaims 32 to 36, wherein the compound of Formula VII is selected from acompound of the formula

wherein X is selected from —O—, —NHC(O)—, —CH₂CHOHCH₂NH—, and —NH—; andn is an integer from 1 to
 30. 38. The compound of any one of claims 32to 37, wherein n is an integer from 1 to
 10. 39. The compound of any oneof claims 1 to 5, wherein R¹ and R³ are taken together with theirintervening atoms to form a fused, optionally substituted heteroaryl oroptionally substituted heterocyclyl.
 40. The compound of claim 39,wherein R¹ and R³ are taken together with their intervening atoms toform a fused, optionally substituted heteroaryl.
 41. The compound ofclaim 39, wherein R¹ and R³ are taken together with their interveningatoms to form a fused, optionally substituted heterocyclyl.
 42. Thecompound of any one of claims 39 to 41, wherein the heteroaryl orheterocyclyl is substituted with an optionally substituted amino group.43. The compound of any one of claims 39 to 42, wherein the compound ofFormula I is selected from a compound of the formula:

wherein n is an integer from 1 to
 30. 44. The compound of claim 43,wherein n is an integer from 1 to
 10. 45. The compound of any one ofclaims 1 to 5, wherein R³ is OH.
 46. The compound of claim 45, whereinR¹ is selected optionally substituted alkyl, optionally substitutedaryl, and —X-POLY.
 47. The compound of claim 45 or 46, wherein R¹ isoptionally substituted lower alkyl.
 48. The compound of any one ofclaims 45 to 47, wherein R¹ is optionally substituted methyl.
 49. Thecompound of any one of claims 45 to 48, wherein the compound of FormulaI is selected from a compound of the formula

wherein n is an integer from 1 to
 30. 50. The compound of claim 49,wherein n is 1 to
 10. 51. The compound of claim 45 or 46, wherein R¹ is,selected from phenyl substituted with 1 to 3 substituents chosen fromhalo and —X-POLY.
 52. The compound of claim 51, wherein R¹ is selectedfrom phenyl substituted with 1 to 3 substituents chosen from halo and—O—(CH₂CH₂O)_(n)CH₃, where n is an integer from 1 to 30
 53. The compoundof any one of claims 51 or 52, wherein the compound of Formula I isselected from a compound of the formula:

wherein n is an integer from 1 to
 30. 54. The compound of claim 53,wherein n is an integer from 1 to
 10. 55. A compound any one of claims 1and 3 to 6, wherein R³ is —OH and R⁵ is —X-POLY.
 56. A compound of claim55, wherein the compound of Formula I is a compound of the formula

wherein X is selected from O and NH and n is an integer from 1 to 30.57. The compound of claim 56, wherein n is an integer from 1 to
 10. 58.The compound of claim 1, wherein R² is —X-POLY.
 59. The compound ofclaim 58, wherein G is O and

is a double bond.
 60. The compound of claim 58 or 59, wherein R¹ ishydrogen.
 61. The compound of any one of claims 58 to 60, wherein R⁵ ishydrogen.
 62. The compound of claim 58 to 61, wherein R³ is —OH.
 63. Thecompound of any one of claims 58 to 63, wherein the compound of FormulaI is a compound of the formula:

wherein: X is selected from a covalent bond and —C(O)—; and POLY is apoly(alkylene oxide) oligomer.
 64. The compound of any one of claims 58to 64, wherein the compound of Formula I is a compound of the formula:

wherein n is an integer from 1 to
 30. 65. The compound of claim 64,wherein n is an integer from 1 to
 10. 66. The compound of claim 1,wherein

is a single bond.
 67. The compound of claim 66, wherein R¹ is hydrogen.68. The compound of claim 66 or 67, wherein R² is cyclopropylmethyl. 69.The compound of any one of claims 66 to 68, wherein R³ is —OH.
 70. Thecompound of any one of claims 66 to 69, wherein R⁵ is hydrogen.
 71. Thecompound of any one of claims 66 to 70, wherein the compound of FormulaI is selected from a compound of the formula:

wherein: AA is an amino acid residue; and n is an integer from 1 to 30.72. The compound of claim 71, wherein AA is a glycine residue.
 73. Thecompound of claim 71 or claim 72, wherein n is 1 to
 10. 74. The compoundof claim 8, wherein R³ is amino substituted with a substituted loweralkyl.
 75. The compound of claim 74, wherein the compound of Formula Iis selected from a compound of the formula

wherein: q is an integer from 1 to 3; each R^(a) is independentlyselected from optionally substituted amino, halo, optionally substitutedalkyl, and X—(CH₂CH₂O)_(n)CH₃; X is selected from a covalent bond, —NH—or —O—; n is an integer from 1 to 30; wherein one R^(a) is—X—(CH₂CH₂O)_(n)CH₃.
 76. The compound of claim 75, wherein q is
 1. 77.The compound of claim 75 or 76, wherein X is —O—.
 78. The compound ofany one of claims 75 to 77, wherein the compound of Formula XV is chosenfrom a compound of the formula:

wherein n is an integer from 1 to
 30. 79. The compound of claim 78,wherein n is an integer from 1 to
 10. 80. The compound of any one ofclaims 1 to 6, wherein R³ is an optionally substituted heterocyclyl. 81.The compound of any claim 80, wherein the heterocyclyl is substitutedwith —X-POLY.
 82. The compound of claim 80 or 81, wherein R³ is apiperazinyl group substituted with —X-POLY.
 83. The compound of any oneof claims 80 to 82, wherein the compound of Formula I is a compound ofthe formula

wherein n is 1 to
 30. 84. The compound of claim 83, wherein n is 1 to10.
 85. The compound of any one of claims 1 and 3-6, wherein R³ and R⁵are taken together with their intervening atoms to form a fused,optionally substituted heteroaryl.
 86. The compound of claim 85, whereinthe heteroaryl is substituted with an optionally substituted aminogroup.
 87. The compound of any one of claims 85 and 86, wherein thecompound of Formula I is selected from a compound of the formula:

wherein n is an integer from 1 to
 30. 88. The compound of claim 87,wherein n is an integer from 1 to
 10. 89. The compound of any one ofclaims 1 to 9, wherein the compound is selected from a compound of theformula

wherein R⁶ is an optionally substituted alkyl or an optionallysubstituted heterocyclyl.
 90. The compound of claim 89, wherein R⁶ is anoptionally substituted lower alkyl.
 91. The compound of any one ofclaims 89 or 90, wherein R⁶ is a lower alkyl substituted with one tofive substituents selected from hydroxyl, lower alkoxy, halogen, andlower alkyl.
 92. The compound of any one of claims 89 to 91, wherein R⁶is an isopropyl or t-butyl group, substituted with 1 to 3 hydroxylgroups.
 93. The compound of claim 89, R⁶ is a heterocyclyl substitutedwith —X—(CH₂CH₂O)_(n)CH₃; wherein X is selected from a covalent bond,—NH— or —O—; and n is an integer from 1 to
 30. 94. The compound of claim93, wherein R⁶ is a piperidinyl group substituted with—X—(CH₂CH₂O)_(n)CH₃; wherein X is selected from a covalent bond, —NH— or—O—; and n is an integer from 1 to
 30. 95. The compound of claim 93 or94, wherein R⁶ is a piperidinyl group substituted with—X—(CH₂CH₂O)_(n)CH₃; wherein X is a covalent bond; and n is an integerfrom 1 to
 10. 96. The compound of any of one claims 93 to 95, whereinthe substituted heterocyclyl group is a substituted piperidin-4-yl. 97.The compound of any one of claims 66 to 70, wherein the compound ofFormula I is selected from a compound of the formula:

wherein: X is a covalent bond; and n is an integer from 1 to
 30. 98. Thecompound of claim 97, wherein n is an integer from 1 to
 10. 99. Acompound having the following structure:

n is an integer from 1 to 30, and pharmaceutically acceptable saltsthereof.
 100. A compound, selected from(2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R,11R)-3-(Cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;(2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one;(2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide;(2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide;N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide;(2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one;(2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol;(2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;(2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;and(2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one,and pharmaceutically acceptable salts thereof.
 101. A pharmaceuticalcomposition comprising a compound of any one of the preceding claims andat least one pharmaceutically acceptable excipient.
 102. A compositionof matter comprising a compound of any one of the preceding claims,wherein the compound is present in a dosage form.
 103. A methodcomprising administering a compound of any one of the preceding claimsto a patient in need thereof.